Contingent cardio-protection for epilepsy patients

ABSTRACT

Disclosed are methods and systems for treating epilepsy by stimulating a main trunk of a vagus nerve, or a left vagus nerve, when the patient has had no seizure or a seizure that is not characterized by cardiac changes such as an increase in heart rate, and stimulating a cardiac branch of a vagus nerve, or a right vagus nerve, when the patient has had a seizure characterized by cardiac changes such as a heart rate increase.

CROSS-REFERENCE TO RELATED APPLICATIONS

This presently being filed application is a continuation-in-part of andclaims priority to co-pending U.S. patent application Ser. No.15/788,078 entitled “Programmable Autotitrating of Electrical Parametersof Implantable Medical Device”, filed on Oct. 19, 2017, which is acontinuation of and claims priority to U.S. patent application Ser. No.14/203,394 entitled “Programmable Autotitrating of Electrical Parametersof Implantable Medical Device”, filed on Mar. 10, 2014 and claimspriority to U.S. Provisional Application No. 61/799,046 filed on Mar.15, 2013 and this presently being filed application is acontinuation-in-part of and claims priority to co-pending U.S. patentapplication Ser. No. 16/679,216, entitled “Contingent Cardio-ProtectionFor Epilepsy Patients”, filed on Nov. 10, 2019 which is acontinuation-in-part of and claims priority to co-pending U.S. patentapplication Ser. No. 15/437,155 entitled “Contingent Cardio-ProtectionFor Epilepsy Patients”, filed on Feb. 20, 2017, which claims priority toand is a divisional application of U.S. patent application Ser. No.14/050,173 entitled “Contingent Cardio-Protection For EpilepsyPatients”, filed on Oct. 9, 2013 (now U.S. Pat. No. 9,579,506), whichclaims priority to and is a continuation-in-part of U.S. patentapplication Ser. No. 13/601,099 entitled “Contingent Cardio-ProtectionFor Epilepsy Patients”, filed on Aug. 31, 2012 (now U.S. Pat. No.9,314,633), which claims priority to and is a continuation-in-part ofU.S. patent application Ser. No. 12/020,195 entitled “Method, Apparatusand System for Bipolar Charge Utilization during Stimulation by anImplantable Medical Device”, filed on Jan. 25, 2008 (now U.S. Pat. No.8,260,426) and claims priority to and is a continuation-in-part of U.S.patent application Ser. No. 12/020,097 entitled “Changeable ElectrodePolarity Stimulation by an Implantable Medical Device”, filed on Jan.25, 2008 (now U.S. Pat. No. 8,565,867) all of which are incorporatedherein by reference in their entireties.

BACKGROUND OF THE DISCLOSURE

This disclosure relates generally to medical devices, and, moreparticularly, to methods, apparatus, and systems for performing vagusnerve stimulation (VNS) for treating epileptic seizures characterized bycardiac changes, including ictal tachycardia.

DESCRIPTION OF THE RELATED ART

While seizures are the best known and most studied manifestation ofepilepsy, cardiac alterations are prevalent and may account for the highrate of sudden unexpected death (SUDEP) in these patients. Thesealterations may include changes in rate (most commonly tachycardia,rarely bradycardia or asystole), rhythm (PACs, PVCs,), conduction (e.g.,bundle branch block) and repolarization abnormalities (e.g., Q-Tprolongation, which occurs primarily during (ictal) but also betweenseizures (inter-ictally). In addition, S-T segment depression (a sign ofmyocardial ischemia) is observed during epileptic seizures. Significantelevations in heart-type fatty acid binding protein (H-FABP), acytoplasmic low-molecular weight protein released into the circulationduring myocardial injury have been documented in patients with epilepsyand without evidence of coronary artery disease, not only duringseizures but also during free-seizure periods. H-FABP is a moresensitive and specific marker of myocardial ischemia than troponin I orCK-MB. Elevations in H-FABP appear to be un-correlated with duration ofillness, of the recorded seizures, or with the Chalfont severity scoreof the patients.

The cardiac alterations in epilepsy patients, both during and betweenseizures, have a multi-factorial etiology, but a vago-sympatheticimbalance seems to play a prominent role in their generation. Themajority of epileptic seizures enhance the sympathetic tone (plasmanoradrenaline and adrenaline rise markedly after seizure onset) causingtachycardia, arterial hypertension and increases in the respiratoryrate, among others. Recurrent and frequent exposure to the outpouring ofcatecholamines associated with seizures in patients withpharmaco-resistant epilepsies may, for example, account forabnormalities that increase the risk of sudden death such asprolongation of the Q-T interval which leads to often fataltachyarrhythmias such as torsade de pointe. Further evidence in supportof the role of catecholamines in SUDEP is found in autopsies of SUDEPvictims, revealing interstitial myocardial fibrosis (a risk factor forlethal arrhythmias), myocyte vacuolization, atrophy of cardiomyocytes,leukocytic infiltration, and perivascular fibrosis. Restoration of thesympathetic-parasympathetic tone to normal levels, a therapeuticobjective that may be accomplished by enhancing parasympathetic activitythrough among others, electrical stimulation of the vagus nerve, maydecrease the rate and severity of cardiac and autonomic co-morbiditiesin these patients.

While there have been significant advances over the last several decadesin treatments for epileptic seizures, the management ofco-morbidities—in particular the cardiac alterations associated withseizures—remains largely unaddressed. There is a need for improvedepilepsy treatments that address cardiac impairments associated withseizures. Pharmacological therapies for neurological diseases (includingepilepsy) have been available for many decades. A more recent treatmentfor neurological disorders involves electrical stimulation of a targettissue to reduce symptoms or effects of the disorder. Such therapeuticelectrical signals have been successfully applied to brain, spinal cord,and cranial nerves tissues improve or ameliorate a variety ofconditions. A particular example of such a therapy involves applying anelectrical signal to the vagus nerve to reduce or eliminate epilepticseizures, as described in U.S. Pat. Nos. 4,702,254, 4,867,164, and5,025,807, which are hereby incorporated herein by reference in theirentirety.

The endogenous electrical activity (i.e., activity attributable to thenatural functioning of the patient's own body) of a neural structure maybe modulated in a variety of ways. One such way is by applying exogenous(i.e., from a source other than the patient's own body) electrical,chemical, or mechanical signals to the neural structure. In someembodiments, the exogenous signal (“neurostimulation” or“neuromodulation”) may involve the induction of afferent actionpotentials, efferent action potentials, or both, in the neuralstructure. In some embodiments, the exogenous (therapeutic) signal mayblock or interrupt the transmission of endogenous (natural) electricalactivity in the target neural structure. Electrical signal therapy maybe provided by implanting an electrical device underneath the skin of apatient and delivering an electrical signal to a nerve such as a cranialnerve.

In one embodiment, the electrical signal therapy may involve detecting asymptom or event associated with the patient's medical condition, andthe electrical signal may be delivered in response to the detection.This type of stimulation is generally referred to as “closed-loop,”“active,” “feedback,” “contingent” or “triggered” stimulation.Alternatively, the system may operate according to a predeterminedprogram to periodically apply a series of electrical pulses to the nerveintermittently throughout the day, or over another predetermined timeinterval. This type of stimulation is generally referred to as“open-loop,” “passive,” “non-feedback,” “non-contingent” or“prophylactic,” stimulation.

In other embodiments, both open- and closed-loop stimulation modes maybe used. For example, an open-loop electrical signal may operate as a“default” program that is repeated according to a programmed on-time andoff-time until a condition is detected by one or more body sensorsand/or algorithms. The open-loop electrical signal may then beinterrupted in response to the detection, and the closed-loop electricalsignal may be applied—either for a predetermined time or until thedetected condition has been effectively treated. The closed-loop signalmay then be interrupted, and the open-loop program may be resumed.Therapeutic electrical stimulation may be applied by an implantablemedical device (IMD) within the patient's body or, in some embodiments,externally.

Closed-loop stimulation of the vagus nerve has been proposed to treatepileptic seizures. Many patients with intractable, refractory seizuresexperience changes in heart rate and/or other autonomic body signalsnear the clinical onset of seizures. In some instances the changes mayoccur prior to the clinical onset, and in other cases the changes mayoccur at or after the clinical onset. Where the changes involves heartrate, most often the rate increases, although in some instances a dropor a biphasic change (up-then-down or down-then-up) may occur. It ispossible using a heart rate sensor to detect such changes and toinitiate therapeutic electrical stimulation (e.g., VNS) based on thedetected change. The closed-loop therapy may be a modified version of anopen-loop therapy. See, e.g., U.S. Pat. Nos. 5,928,272, and 6,341,236,each hereby incorporated by reference herein. The detected change mayalso be used to warn a patient or third party of an impending oroccurring seizure.

VNS therapy for epilepsy patients typically involves a train ofelectrical pulses applied to the nerve with an electrode pair includinga cathode and an anode located on a left or right main vagal trunk inthe neck (cervical) area. Only the cathode is capable of generatingaction potentials in nerve fibers within the vagus nerve; the anode mayblock some or all of the action potentials that reach it (whetherendogenous or exogenously generated by the cathode). VNS as an epilepsytherapy involves modulation of one or more brain structures. Therefore,to prevent the anode from blocking action potentials generated by thecathode from reaching the brain, the cathode is usually located proximalto the brain relative to the anode. For vagal stimulation in the neckarea, the cathode is thus usually the upper electrode and the anode isthe lower electrode. This arrangement is believed to result in partialblockage of action potentials distal to or below the anode (i.e., thosethat would travel through the vagus nerve branches innervating thelungs, heart and other viscerae). Using an upper-cathode/lower-anodearrangement has also been favored to minimize any effect of the vagusnerve stimulation on the heart.

Stimulation of the left vagus nerve, for treatment of epilepsy hascomplex effects on heart rate (see Frei & Osorio, Epilepsia 2001), oneof which includes slowing of the heart rate, while stimulation of theright vagus nerve has a more prominent bradycardic effect. Electricalstimulation of the right vagus nerve has been proposed for use in theoperating room to slow the heart during heart bypass surgery, to providea surgeon with a longer time period to place sutures between heartbeats(see, e.g., U.S. Pat. No. 5,651,373). Some patents discussing VNStherapy for epilepsy treatment express concern with the risk ofinadvertently slowing the heart during stimulation. In U.S. Pat. No.4,702,254, it is suggested that by locating the VNS stimulationelectrodes below the inferior cardiac nerve, “minimal slowing of theheart rate is achieved” (col. 7 lines 3-5), and in U.S. Pat. No.6,920,357, the use of a pacemaker to avoid inadvertent slowing of theheart is disclosed.

Cranial nerve stimulation has also been suggested for disorders outsidethe brain such as those affecting the gastrointestinal system, thepancreas (e.g., diabetes, which often features impaired production ofinsulin by the islets of Langerhans in the pancreas), or the kidneys.Electrical signal stimulation of either the brain alone or the organalone may have some efficacy in treating such medical conditions, butmay lack maximal efficacy.

While electrical stimulation has been used for many years to treat anumber of conditions, a need exists for improved VNS methods of treatingepilepsy and its cardiac co-morbidities as well as other brain andnon-brain disorders.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising receiving at least one body datastream, analyzing the at least one body data stream using a seizure orevent detection algorithm to detect whether or not the patient is havingand/or has had an epileptic seizure, receiving a cardiac signal of thepatient, applying a first electrical signal to a vagus nerve of thepatient based on a determination that the patient is not having and/orhas not had an epileptic seizure characterized by a decrease in thepatient's heart rate, wherein the first electrical signal is not a vagusnerve conduction blocking electrical signal, and applying a secondelectrical signal to a vagus nerve of the patient based on adetermination that the patient is having and/or has had an epilepticseizure characterized by a decrease in the patient's heart rate, whereinthe second electrical signal is a pulsed electrical signal that blocksaction potential conduction in the vagus nerve.

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising sensing a cardiac signal and akinetic signal of the patient, analyzing at least one of the cardiacsignal and the kinetic signal; determining whether or not the patienthas had an epileptic seizure based on the analyzing; in response to adetermination that the patient has had an epileptic seizure, determiningwhether or not the seizure is characterized by a decrease in thepatient's heart rate, applying a first electrical signal to a vagusnerve of the patient based on a determination that the patient has hadan epileptic seizure characterized by a decrease in the patient's heartrate, wherein the first electrical signal is a pulsed electrical signalthat blocks action potential conduction in the vagus nerve; and applyinga second electrical signal to a vagus nerve of the patient based on oneof a) a determination that the patient has not had an epileptic seizure,and b) a determination that the patient has had an epileptic seizurethat is not characterized by a decrease in the patient's heart rate,wherein the second electrical signal is not a vagus nerve conductionblocking electrical signal.

In one aspect, the present disclosure relates to a system for treating amedical condition in a patient, comprising at least one electrodecoupled to a vagus nerve of the patient, a programmable electricalsignal generator, a sensor for sensing at least one body data stream, aseizure detection module capable of analyzing the at least one body datastream and determining, based on the analyzing, whether or not thepatient is having and/or has had an epileptic seizure, a heart ratedetermination unit capable of determining a heart rate of a patientproximate in time to an epileptic seizure detected by the seizuredetection module, and a logic unit for applying a first electricalsignal to the vagus nerve using the at least one electrode based on adetermination by the seizure detection module that the patient is havingand/or has had an epileptic seizure characterized by a decrease in thepatient's heart rate, wherein the first electrical signal is a pulsedelectrical signal that blocks action potential conduction in the vagusnerve, and for applying a second electrical signal to the vagus nerveusing the at least one electrode as a cathode based upon one of a) adetermination that the patient is not having and/or has not had anepileptic seizure, and b) a determination that the patient is havingand/or has had an epileptic seizure that is not characterized by adecrease in the patient's heart rate, wherein the second electricalsignal is not a vagus nerve conduction blocking electrical signal. Inone embodiment, the seizure detection module may comprise the heart ratedetermination unit.

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising applying a first electrical signal toa vagus nerve of the patient, wherein the first electrical signal is anopen-loop electrical signal having a programmed on-time and a programmedoff-time, sensing at least one body signal of the patient, determiningthe start of an epileptic seizure based on the at least one body signal,determining whether or not the seizure is characterized by a decrease inthe patient's heart rate, applying a second, closed-loop electricalsignal to a vagus nerve of the patient based on a determination that theepileptic seizure is not characterized by a decrease in the patient'sheart rate, and applying a third, closed-loop electrical signal to avagus nerve of the patient based on a determination that the seizure ischaracterized by a decrease in the patient's heart rate, wherein thethird electrical signal is applied to block action potential conductionon the vagus nerve.

In one aspect, the present disclosure relates to a method of controllinga heart rate of an epilepsy patient comprising sensing a kinetic signalof the patient; analyzing said kinetic signal to determine at least onekinetic index; receiving a cardiac signal of the patient; analyzing thecardiac signal to determine the patient's heart rate; determining if thepatient's heart rate is commensurate with the at least one kineticindex; and applying a first electrical signal to a vagus nerve of thepatient based on a determination that the patient's heart rate is notcommensurate with the kinetic index. In one embodiment, the at least onekinetic index comprises at least one of an activity level or an activitytype of the patient, and determining if the heart rate is commensuratewith the kinetic index comprises determining if the heart rate iscommensurate with the at least one of an activity level or an activitytype.

In one aspect, the present disclosure relates to a method of controllinga heart rate of an epilepsy patient comprising sensing at least one of akinetic signal and a metabolic (e.g., oxygen consumption) signal of thepatient; receiving a cardiac signal of the patient; analyzing thecardiac signal to determine the patient's heart rate; determining if thepatient's heart rate is commensurate with the at least one of a kineticand a metabolic signal of the patient; and applying a first electricalsignal to a vagus nerve of the patient based on a determination that thepatient's heart rate is not commensurate with the at least one of akinetic signal and a metabolic signal. In one embodiment, the methodfurther comprises determining at least one of an activity level or anactivity type of the patient based on the at least one of a kinetic anda metabolic signal, and determining if the heart rate is commensuratewith the kinetic signal comprises determining if the heart rate iscommensurate with the at least one of an activity level or an activitytype.

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising sensing at least one body signal ofthe patient; determining whether or not the patient is having or has hadan epileptic seizure based on the at least one body signal; sensing acardiac signal of the patient; determining whether or not the seizure isassociated with a change in the patient's cardiac signal; applying afirst therapy to a vagus nerve of the patient based on a determinationthat the patient is having or has had an epileptic seizure that is notassociated with a change in the patient's cardiac signal, wherein thefirst therapy is selected from an electrical, chemical, mechanical(e.g., pressure) or thermal signal. The method further comprisesapplying a second therapy to a vagus nerve of the patient based on adetermination that the patient has had an epileptic seizure associatedwith a change in the patient's cardiac signal, wherein the secondtherapy is selected from an electrical, chemical, mechanical (e.g.,pressure) or thermal signal. In some embodiments, a third therapy may beapplied to a vagus nerve based a determination that the patient has nothad an epileptic seizure, wherein the third therapy is selected form anelectrical, chemical, mechanical or thermal signal.

In some embodiments, the present disclosure relates to a method ofautomatically titrating an electrical therapy administered to a patientby an implanted medical device to a target dosage, comprising:programming the medical device with an electrical therapy, wherein theprogrammed electrical therapy comprises a first target value for a firstelectrical therapy parameter defining the electrical therapy;programming at least one titration parameter for automatically adjustingthe first electrical therapy parameter from a first value to the firsttarget value over a titration time period of at least two days, whereinthe at least one titration parameter is selected from the titration timeperiod, a titration step interval, and a titration step magnitude;initiating the electrical therapy, wherein the first electrical therapyparameter comprises said first value; and automatically titrating theelectrical therapy by making a plurality of adjustments to the value ofthe first electrical therapy parameter, whereby the first electricaltherapy parameter is changed from the first value to the first targetvalue according to a titration function.

In some embodiments, the present disclosure relates to a method ofautomatically titrating an electrical therapy administered to a patientby an implanted medical device to a target dosage, comprising:programming the medical device with an electrical therapy, whereinprogramming comprises providing a first target value for a firstelectrical therapy parameter characterizing the electrical therapy;programming at least one titration parameter for automatically adjustingthe first electrical therapy parameter from a first value to the firsttarget value over a titration time of at least five days, wherein the atleast one titration parameter is selected from the titration timeperiod, a titration step interval, and a titration step magnitude;initiating the electrical therapy, wherein the first electrical therapyparameter comprises said first value; automatically titrating theelectrical therapy by making a plurality of adjustments to the value ofthe at least a first electrical therapy parameter, whereby the firstelectrical therapy parameter is changed from the first value to thefirst target value according to a first titration function; receiving abody signal after at least one of said plurality of adjustments to thevalue of the first electrical therapy parameter; determining whetherthere is an adverse effect associated with the at least one of saidplurality of adjustments, based upon said body signal; returning thevalue of said first electrical therapy parameter to a prior value toprovide a prior electrical therapy program, in response to determiningthat there is an adverse effect associated with said at least one ofsaid plurality of adjustments; and providing said prior electricaltherapy program to said patient. In one embodiment, the adverse effectis selected from discomfort, pain, dyspnea, voice alteration, increasedheart rate, and decreased heart rate.

In some embodiments, the present disclosure relates to a medical devicesystem for providing an electrical therapy, comprising: a programmer forprogramming an implantable medical device with an electrical therapy,wherein the programmer enables a user to program into the medical devicea first value for a first electrical therapy parameter characterizingthe electrical therapy, a first target value for the first electricaltherapy parameter, and at least one titration parameter forautomatically adjusting the first electrical therapy parameter from afirst value to the first target value over a titration time period of atleast two days, wherein the at least one titration parameter is selectedfrom the titration time period, a titration step interval, and atitration step magnitude; an electrode configured to deliver anelectrical therapy characterized by a plurality of parameters to apatient; and an implantable medical device, comprising: an electricaltherapy module to provide the electrical therapy to the patient usingsaid electrode; and a therapy titration module configured toautomatically titrate the electrical therapy by making a plurality ofadjustments to the value of the first electrical therapy parameter,whereby the first electrical therapy parameter is changed from the firstvalue to the first target value according to a titration function. Inone embodiment, the implantable medical device may comprise a body datamodule capable of receiving a body signal from the patient, a feedbackmodule configured to provide feedback data to the therapy titrationmodule, wherein the feedback data is based upon one of said body dataand a manual input from the patient or a caregiver, and wherein thetherapy titration module comprises a dynamic adjustment unit configureto return the value of the first electrical therapy parameter to aprevious value after at least a first adjustment, based on said feedbackdata.

In some embodiments, the present disclosure relates to a non-transitorycomputer readable program storage unit encoded with instructions that,when executed by a computer, perform a method as described above.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure may be understood by reference to the followingdescription taken in conjunction with the accompanying drawings, inwhich like reference numerals identify like elements, and in which:

FIGS. 1A-1E provide stylized diagrams of an implantable medical deviceimplanted into a patient's body for providing first and secondelectrical signals to a vagus nerve of a patient for treating epilepticseizures, in accordance with one illustrative embodiment of the presentdisclosure;

FIG. 2 illustrates a block diagram depiction of an implantable medicaldevice of FIG. 1, in accordance with one illustrative embodiment of thepresent disclosure;

FIG. 3 illustrates a block diagram depiction of an electrode polarityreversal unit shown in FIG. 2, in accordance with one illustrativeembodiment of the present disclosure;

FIG. 4 illustrates a flowchart depiction of a method for providing firstand second electrical signals to a main trunk and a cardiac branch of avagus nerve, respectively, based upon whether or not the patient ishaving and/or has had an epileptic seizure, in accordance with anillustrative embodiment of the present disclosure;

FIG. 5 illustrates a flowchart depiction of a method for providing firstand second electrical signals to a main trunk and a cardiac branch of avagus nerve, respectively, based upon whether or not at least one of acardiac signal and a kinetic signal indicates that the patient is havingand/or has had an epileptic seizure, and whether the seizure ischaracterized by an increase in heart rate, in accordance with anillustrative embodiment of the present disclosure;

FIG. 6 illustrates a flowchart depiction of a method for providing afirst, open-loop electrical signal to a main trunk of a vagus nerve, asecond, closed-loop electrical signal to the main trunk of the vagusnerve based upon the patient having had an epileptic seizure notcharacterized by an increase in heart rate, and a third, closed-loopelectrical signal to a cardiac branch of a vagus nerve based upon thepatient having had an epileptic seizure characterized by an increase inheart rate, in accordance with an illustrative embodiment of the presentdisclosure; and

FIG. 7 is a flowchart depiction of a method for providing closed-loopvagus nerve stimulation for a patient with epilepsy by stimulating aright vagus nerve in response to detecting a seizure with tachycardiaand stimulating a left vagus nerve in the absence of such a detection.For example if a recumbent person's heart rate is 55 bpm and itincreases to 85 during a seizure, this is not clinical/pathologicaltachycardia, but may be considered tachycardia within the meaning ofsome embodiments of the present disclosure.

FIG. 8 is a flowchart depiction of a method for providing a closed-looptherapy to a vagus nerve of a patient with epilepsy in response todetecting a seizure associated with a heart rate decrease, wherein saidtherapy blocks impulse conduction along at least one vagus nerve.

FIG. 9 is a flowchart depicting a method for providing closed-loop vagusnerve stimulation based on an assessment of whether the patient's heartrate is commensurate with the patient's activity level or activity type.

FIG. 10 is a flowchart depicting a method for providing closed-loopvagus nerve stimulation based on a determination that the patient'sheart rate is incommensurate with the patient's activity level oractivity type, and further in view of whether the incommensurate changesinvolves relative tachycardia or relative bradycardia.

FIG. 11 is a graph of heart rate versus time, according to oneembodiment.

FIG. 12 is another graph of heart rate versus time, according to oneembodiment.

FIG. 13 is another graph of heart rate versus time, according to oneembodiment.

FIG. 14 is another graph of heart rate versus time, according to oneembodiment.

FIG. 15 is another graph of heart rate versus time, according to oneembodiment.

FIG. 16 is a flowchart of a therapy procedure, according to oneembodiment.

FIG. 17 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 18 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 19 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 20 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 21 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 22 shows a schematic diagram of a medical device system, inaccordance with some embodiments of the present disclosure;

FIG. 23 shows a schematic diagram of data acquisition components of amedical device system, in accordance with some embodiments of thepresent disclosure;

FIG. 24 shows a schematic diagram of a therapy titration module,according to some embodiments of the present disclosure;

FIG. 25 shows a schematic diagram of a dynamic adjustment unit,according to some embodiments of the present disclosure;

FIG. 26 shows an example of a titration comprising a series ofincreasing adjustments to a first electrical parameter from a firstvalue to a first target value, according to some embodiments of thepresent disclosure;

FIG. 27 shows examples of a titration of a first electrical parameterinvolving a dynamic adjustment to a programmed titration, according tosome embodiments of the present disclosure;

FIG. 28 shows a flowchart depiction of a method, according to someembodiments of the present disclosure;

FIG. 29 shows a flowchart depiction of a method, according to someembodiments of the present disclosure;

FIG. 30 shows a flowchart depiction of a method for performing atitration process, according to some embodiments of the presentdisclosure;

FIG. 31 shows a flowchart depiction of a method for implementing atitration interrupt and/or a multi-titration process, according to someembodiments of the present disclosure;

FIG. 32 shows exemplary titration functions for two parameters,according to some embodiments of the present disclosure; and

FIG. 33 shows an exemplary titration function, according to someembodiments of the present disclosure.

While the disclosure is susceptible to various modifications andalternative forms, specific embodiments thereof have been shown by wayof example in the drawings and are herein described in detail. It shouldbe understood, however, that the description herein of specificembodiments is not intended to limit the disclosure to the particularforms disclosed, but on the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the disclosure as defined by the appended claims.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

Illustrative embodiments of the disclosure are described herein. Forclarity, not all features of an actual implementation are provided indetail. In any actual embodiment, numerous implementation-specificdecisions must be made to achieve the design-specific goals. Such adevelopment effort, while possibly complex and time-consuming, wouldnevertheless be a routine task for persons of skill in the art giventhis disclosure.

This application does not intend to distinguish between components thatdiffer in name but not function. “Including” and “includes” are used inan open-ended fashion, and should be interpreted to mean “including, butnot limited to.” “Couple” or “couples” are intended to mean either adirect or an indirect electrical connection. “Direct contact,” “directattachment,” or providing a “direct coupling” indicates that a surfaceof a first element contacts the surface of a second element with nosubstantial attenuating medium there between. Small quantities ofsubstances, such as bodily fluids, that do not substantially attenuateelectrical connections do not vitiate direct contact. “Or” is used inthe inclusive sense (i.e., “and/or”) unless a specific use to thecontrary is explicitly stated.

“Electrode” or “electrodes” may refer to one or more stimulationelectrodes (i.e., electrodes for applying an electrical signal generatedby an IMD to a tissue), sensing electrodes (i.e., electrodes for sensinga body signal), and/or electrodes capable of either stimulation orsensing. “Cathode” and “anode” have their standard meanings, as theelectrode at which current leaves the IMD system and the electrode atwhich current enters the IMD system, respectively. Reversing thepolarity of the electrodes can be effected by any switching techniqueknown in the art.

A “pulse” is used herein to refer to a single application of electricalcharge from the cathode to target neural tissue. A pulse may includeboth a therapeutic portion (in which most or all of the therapeutic oraction-potential-generating effect occurs) and a charge-balancingportion in which the polarity of the electrodes are reversed and theelectrical current is allowed to flow in the opposite direction to avoidelectrode and/or tissue damage. Individual pulses are separated by atime period in which no charge is delivered to the nerve, which can becalled the “interpulse interval.” A “burst” is used herein to refer to aplurality of pulses, which may be separated from other bursts by aninterburst interval in which no charge is delivered to the nerve. Theinterburst intervals have a duration exceeding the interpulse intervalduration. In one embodiment, the interburst interval is at least twiceas long as the interpulse interval. The time period between the end ofthe last pulse of a first burst and the initiation of the first pulse ofthe next subsequent burst can be called the “interburst interval.” Inone embodiment, the interburst interval is at least 100 msec.

A plurality of pulses can refer to any of (a) a number of consecutivepulses within a burst, (b) all the pulses of a burst, or (c) a number ofconsecutive pulses including the final pulse of a first burst and thefirst pulse of the next subsequent burst.

“Stimulate,” “stimulating” and “stimulator” may generally refer toapplying a signal, stimulus, or impulse to neural tissue (e.g., a volumeof neural tissue in the brain or a nerve) for affecting it neuronalactivity. While the effect of such stimulation on neuronal activity istermed “modulation,” for simplicity, the terms “stimulating” and“modulating”, and variants thereof, are sometimes used interchangeablyherein. The modulation effect of a stimulation signal on neural tissuemay be excitatory or inhibitory, and may potentiate acute and/orlong-term changes in neuronal activity. For example, the modulationeffect of a stimulation signal may comprise: (a) initiating actionpotentials in the target neural tissue; (b) inhibition of conduction ofaction potentials (whether endogenous or exogenously generated, orblocking their conduction (e.g., by hyperpolarizing or collisionblocking), (c) changes in neurotransmitter/neuromodulator release oruptake, and (d) changes in neuroplasticity or neurogenesis of braintissue. Applying an electrical signal to an autonomic nerve may comprisegenerating a response that includes an afferent action potential, anefferent action potential, an afferent hyperpolarization, an efferenthyperpolarization, an afferent sub-threshold depolarization, and/or anefferent sub-threshold depolarization. The terms tachycardia andbradycardia are used here in a relative (i.e., any decrease or decreasein heart rate relative to a reference value) or in an absolute sense(i.e., a pathological change relative to a normative value). Inparticular, “tachycardia is used interchangeably with an increase heartrate and “bradycardia” may be used interchangeably with a decrease inheart rate.

A variety of stimulation therapies may be provided in embodiments of thepresent disclosure. Different nerve fiber types (e.g., A, B, andC-fibers that may be targeted) respond differently to stimulation fromelectrical signals because they have different conduction velocities andstimulation threshold. Certain pulses of an electrical stimulationsignal, for example, may be below the stimulation threshold for aparticular fiber and, therefore, may generate no action potential. Thus,smaller or narrower pulses may be used to avoid stimulation of certainnerve fibers (such as C-fibers) and target other nerve fibers (such as Aand/or B fibers, which generally have lower stimulation thresholds andhigher conduction velocities than C-fibers). Additionally, techniquessuch as a pre-pulse may be employed wherein axons of the target neuralstructure may be partially depolarized (e.g., with a pre-pulse orinitial phase of a pulse) before a greater current is delivered to thetarget (e.g., with a second pulse or an initial phase such a stair steppre-pulse to deliver a larger quantum of charge). Furthermore, opposingpolarity phases separated by a zero current phase may be used to exciteparticular axons or postpone nerve fatigue during long term stimulation.

Cranial nerve stimulation, such as vagus nerve stimulation (VNS), hasbeen proposed to treat a number of medical conditions, includingepilepsy and other movement disorders, depression and otherneuropsychiatric disorders, dementia, traumatic brain injury, coma,migraine headache, obesity, eating disorders, sleep disorders, cardiacdisorders (such as congestive heart failure and atrial fibrillation),hypertension, endocrine disorders (such as diabetes and hypoglycemia),and pain, among others. See, e.g., U.S. Pat. Nos. 4,867,164; 5,299,569;5,269,303; 5,571,150; 5,215,086; 5,188,104; 5,263,480; 6,587,719;6,609,025; 5,335,657; 6,622,041; 5,916,239; 5,707,400; 5,231,988; and5,330,515. Despite the variety of disorders for which cranial nervestimulation has been proposed or suggested, the fact that detailedneural pathways for many (if not all) cranial nerves remain relativelyunknown, makes predictions of efficacy for any given disorder difficultor impossible. Even if such pathways were known, the precise stimulationparameters that would modulate particular pathways relevant to aparticular disorder generally cannot be predicted.

Cardiac signals suitable for use in embodiments of the presentdisclosure may comprise one or more of an electrical (e.g., EKG),acoustic (e.g., phonocardiogram or ultrasound/ECHO), force or pressure(e.g., apexcardiogram), arterial pulse pressure and waveform or thermalsignals that may be recorded and analyzed to extract features such asheart rate, heart rate variability, rhythm (regular, irregular, sinus,ventricular, ectopic, etc.), morphology, etc.

It appears that sympatho-vagal imbalance (lower vagal and highersympathetic tone) plays an important role in generation of a widespectrum of ictal and interictal alterations in cardiac dynamics,ranging from rare unifocal PVCs to cardiac death. Without being bound bytheory, restoration of the vagal tone to a level sufficient tocounteract the pathological effects of elevated catecholamines may servea cardio-protective purpose that would be particularly beneficial inpatients with pharmaco-resistant epilepsies, who are at highest risk forSUDEP.

In one embodiment, the present disclosure provides methods and apparatusto increase cardiac vagal tone in epilepsy patients by timely deliveringtherapeutic electrical currents to the trunks of the right or left vagusnerves or to their cardiac rami (branches), in response to increases insympathetic tone, by monitoring among others, heart rate, heart rhythm,EKG morphology, blood pressure, skin resistance, catecholamine or theirmetabolites and neurological signals such as EEG/ECoG, kinetic (e.g.,amplitude velocity, direction of movements) and cognitive (e.g., complexreaction time).

In one embodiment, the present disclosure provides a method of treatinga medical condition selected from the group consisting of epilepsy,neuropsychiatric disorders (including but not limited to depression),eating disorders/obesity, traumatic brain injury, addiction disorders,dementia, sleep disorders, pain, migraine, endocrine/pancreaticdisorders (including but not limited to diabetes), motility disorders,hypertension, congestive heart failure/cardiac capillary growth, hearingdisorders, angina, syncope, vocal cord disorders, thyroid disorders,pulmonary disorders, gastrointestinal disorders, kidney disorders, andreproductive endocrine disorders (including infertility).

FIGS. 1A-1E depict a stylized implantable medical system 100 forimplementing one or more embodiments of the present disclosure. FIGS. 1Aand 1B illustrate an electrical signal generator 110 having main body112 comprising a case or shell (commonly referred to as a “can”) 121)(FIG. 1B) with a header 116 for connecting to a lead assembly 122. Anelectrode assembly 125, preferably comprising at least an electrodepair, is conductively connected to the distal end of an insulated,electrically conductive lead assembly 122, which preferably comprises aplurality of lead wires (at least one wire for each electrode of theelectrode assembly 125). Lead assembly 122 is attached at its proximalend to one or more connectors on header 116 (FIG. 1B).

Electrode assembly 125 may be surgically coupled to a target tissue fordelivery of a therapeutic electrical signal, which may be a pulsedelectrical signal. The target tissue may be a cranial nerve, such as avagus nerve 127 (FIGS. 1A, 1C-E) or another cranial nerve such as atrigeminal nerve. Electrode assembly 125 includes one or more electrodes125-1, 125-2, 125-3, which may be coupled to the target tissue. Theelectrodes may be made from any of a variety of conductive metals knownin the art, e.g., platinum, iridium, oxides of platinum or iridium, orcombinations of the foregoing. In one embodiment, the target tissue is avagus nerve 127, which may include an upper main trunk portion 127-1above a cardiac branch 127-2, and a lower main trunk portion 127-3 belowthe cardiac branch.

In one embodiment, at least one electrode may be coupled to the maintrunk of the vagus nerve, and at least one electrode 125-2 may becoupled to a cardiac branch 127-2 of the vagus nerve (FIG. 1C). The atleast one main trunk electrode may be coupled to an upper main trunk127-1 (e.g., electrode 125-1, FIG. 1C) or a lower main trunk 127-3(e.g., electrode 125-3). The at least one main trunk electrode (125-1,125-3) may be used as a cathode to provide a first electrical signal tothe upper (127-1) or lower (127-3) main trunk. Cardiac branch electrode125-2 may be used as a cathode to provide a second electrical signal tocardiac branch 127-2. An additional electrode to function as the anodemay be selected from one or more of the other electrodes in electrodeassembly 125, can 121, or a dedicated anode.

In some embodiments (FIGS. 1D, 1E), electrode assembly 125 may include amain trunk electrode pair comprising a cathode 125-1 a and an anode125-1 b for coupling to a main trunk of a vagus nerve 127. The maintrunk electrode pair 125-1 a, 125-1 b may be coupled to an upper maintrunk 127-1 of a vagus nerve (FIG. 1D), or to a lower main trunk 127-3(FIG. 1E) for delivering a first electrical signal. Without being boundby theory, it is believed that few or no vagal afferent fibers in thelower main trunk 127-3 pass into cardiac branch 127-2 and, accordingly,that effects of the first electrical signal on cardiac function may beminimized by coupling electrode pair 125-1 a and 125-1 b to the lowermain trunk 127-3 instead of upper main trunk 127-1. Cardiac effects mayalso be minimized by alternative embodiments in which the firstelectrical signal is applied to a lower main trunk 127-3 using a singleelectrode (e.g., 125-3, FIG. 1C) as a cathode and an anode that is notcoupled to the vagus nerve 127 (e.g., by using can 121 as an anode).

In some embodiments (FIGS. 1D, 1E), electrode assembly 125 may include acardiac branch electrode pair comprising a cathode 125-2 a and an anode125-2 b for coupling to a cardiac branch of a vagus nerve. The secondcardiac branch electrode pair may be used to provide a second electricalsignal to a cardiac branch of the nerve to affect the cardiac functionof the patient.

Referring again to FIGS. 1C-1E, a first electrical signal may beprovided to generate afferent action potentials in a main trunk of avagus nerve to modulate electrical activity of the patient's brainwithout significantly affecting the patient's heart rate. The secondelectrical signal may generate efferent action potentials to module thecardiac activity of the patient, and in particular to slow the patient'sheart rate (e.g., to treat an epilepsy patient having seizurescharacterized by ictal tachycardia) and maintain or restore asympathetic/parasympathetic balance to a non-pathological state. Thefirst electrical signal may be applied to the main trunk of the vagusnerve in a variety of ways, so long as at least one electrode is coupledto the main trunk as a cathode. As noted, the cathode may be coupled toeither an upper (127-1) or lower (127-3) main trunk, and an anode may beprovided by any of the other electrodes on the vagus nerve (e.g., 125-1b, 125-2 b, 125-3, FIGS. 1C-1E) or by a separate anode not coupled tothe vagus nerve (e.g., can 121). In one alternative embodiment, anelectrode 125-3 may be coupled to a lower main trunk 127-3 of the vagusnerve to function as an anode. In yet another embodiment, eachindividual electrode element in FIGS. 1A-E (e.g., 125-1, 125-2, 125-3,125-1 a, 125-1 g, 125-2 a, 125-2 b) may comprise an electrode paircomprising both an anode and a cathode. In an additional embodiment,each individual electrode element may comprise three electrodes (e.g.,one serving as cathode and the other two as anodes). Suitable electrodeassemblies are available from Cyberonics, Inc., Houston, Tex., USA asthe Model 302, PerenniaFlex and PerenniaDura electrode assemblies. Inview of the present disclosure, persons of skill in the art willappreciate that many electrode designs could be used in embodiments ofthe present disclosure including unipolar electrodes.

Embodiments of the present disclosure may comprise electrical signalswith either charge-balanced or non-charge-balanced pulses (e.g.,monopolar/monophasic, direct current (DC)). Charge-balanced pulsesinvolve a first phase in which the stimulation occurs (i.e., actionpotentials are induced in target nerve fibers), and a second phase inwhich the polarity of the electrodes are reversed (i.e., the stimulationphase cathode becomes the charge-balancing phase anode, and vice versa).The result is a pulse having two opposite-polarity phases of equalcharge, such that no net charge flows across the electrode during apulse. Charge-balancing is often used to avoid damage to the electrodesthat may result if a pulse results in a net charge flowing across theelectrodes.

In some instances, charge-balancing may involve a passive dischargephase as illustrated in, e.g., FIG. 1A of US Publication 2006/0173493,which is hereby incorporated by reference in its entirety. In passivecharge-balancing, the charge-balancing phase typically involves allowinga capacitor having a charge equal to the charge applied to the nerveduring the stimulation phase to discharge through the polarity-reversedelectrodes. Passive charge-balancing typically uses much lower initialcurrent than the stimulation phase, with the current declining to zeroover a much longer time period than the pulse width of the stimulationphase. A lower current is typically selected in the charge-balancingphase so as to avoid or minimize nerve recruitment during thecharge-balancing phase. In active charge-balancing, the charge-balancingphase is not accomplished by the passive discharge of a capacitor, butby providing a second phase having an opposite polarity but the samecharge magnitude (pulse width multiplied by current) as the first phase.As is usually the case with passive charge-balancing, activecharge-balancing typically involves a much lower current that is appliedover a longer time period than the stimulation phase, so as to avoidnerve recruitment. In some instances, however, the activecharge-balancing phase may be used as a second stimulation phase byselecting a current magnitude of the cathode in the charge-balancingphase (typically a second electrode, which may be the anode of theinitial stimulation phase) that is sufficient to generate actionpotentials in nerve fibers of the target tissue.

Embodiments of the present disclosure may be implemented using passivecharge balancing or active charge-balancing, and the latter may beprovided as a stimulation phase or a non-stimulation phase. Someembodiments may be implemented with non-charge-balanced pulses. Personsof skill in the art, having the benefit of the present disclosure, mayselect the type of charge balancing (if desired) based upon a number offactors including but not limited to whether or not the charge-balancingis intended to affect the cardiac cycle or not, whether afferent orefferent stimulation is desired, the number and location of availableelectrodes for applying the electrical signal, the fibers intended to berecruited during a particular phase and their physiological effects,among many other factors.

In the discussion of electrical signals in the present disclosure,unless otherwise stated, references to electrodes as cathodes or anodesrefers to the polarities of the electrodes during a stimulation phase ofa pulse, whether the pulse is a charge-balanced pulse or anon-charge-balanced pulse (e.g., monopolar/monophasic or DC). It will beappreciated that where charge-balanced pulses are employed, thepolarities will be reversed during a charge-balancing phase. Whereactive charge-balancing is used, cardiac effects may be furtheramplified or ameliorated, depending upon the location of the electrodesbeing used.

Returning to FIG. 1A, in some embodiments, a heart rate sensor 130,and/or a kinetic sensor 140 (e.g., a triaxial accelerometer) may beincluded in the system 100 to sense one or more of a cardiac signal ordata stream and a kinetic data stream of the patient. In one embodiment,the heart rate sensor may comprise a separate element 130 that may becoupled to generator 110 through header 116 as illustrated in FIG. 1A.In another embodiment, the electrodes 125-1, 125-2, 125-3 and/or the can121 may be used as sensing electrodes to sense heart rate. Anaccelerometer may be provided inside generator 110 in one embodiment tosense a kinetic signal (e.g., body movement) of the patient. One or moreof the heart rate sensor 130 and the kinetic sensor 140 may be used by aseizure detection algorithm in the system 100 to detect epilepticseizures. In alternative embodiments, other body signals (e.g., bloodpressure, brain activity, blood oxygen/CO₂ concentrations, temperature,skin resistivity, etc.) of the patient may be sensed and used by theseizure detection algorithm to detect epileptic seizures. Signalgenerator 110 may be implanted in the patient's chest in a pocket orcavity formed by the implanting surgeon below the skin (indicated byline 145, FIG. 1A).

Returning to FIGS. 1A and 1C, a first electrode 125-1 may be wrapped orotherwise electrically coupled to an upper main trunk 127-1 of a vagusnerve 127 of the patient, and a second electrode 125-2 may be wrapped orcoupled to a cardiac branch 127-2 of the vagus nerve. In one embodiment,a third electrode 125-3 may be coupled to a lower main trunk 127-3 ofthe vagus nerve below the cardiac branch 127-2 of the vagus nerve,instead of or in addition to first electrode 125-1 coupled to the uppermain trunk above the cardiac branch. In some embodiments, thirdelectrode 125-3 may be omitted. Electrode assembly 125 may be secured tothe nerve by a spiral anchoring tether 128 (FIG. 1C), which in oneembodiment does not include an electrode but in alternative embodimentsmay contain up to three electrodes that serve as cathode(s) and anode(s)in any possible combination. Lead assembly 122 may further be secured,while retaining the ability to flex, by a suture connection 130 tonearby tissue (FIG. 1C). In particular embodiments, any of first, secondand third electrodes 125-1, 125-2, and 125-3 may be used as either acathode or as an anode. In general, the foregoing electrodes may be usedas a cathode when the particular electrode is the closest electrode(among a plurality of electrodes) to the target organ (e.g., heart,brain, stomach, liver, etc.) to be stimulated. While a single electrode(e.g., 125-1, 125-2, or 125-3) is illustrated in connection with uppermain trunk 127-1, cardiac branch 127-2, and lower main trunk 127-3 inFIGS. 1A and 1C for simplicity, it will be appreciated that one or moreadditional electrodes can be provided on each of the foregoing neuralstructures to provide greater flexibility in stimulation.

In one embodiment, the open helical design of the electrodes 125-1,125-2, 125-3, is self-sizing, flexible, minimize mechanical trauma tothe nerve and allow body fluid interchange with the nerve. The electrodeassembly 125 preferably conforms to the shape of the nerve, providing alow stimulation threshold by allowing a large stimulation contact areawith the nerve. Structurally, the electrode assembly 125 comprises anelectrode ribbon (not shown) for each of electrodes 125-1, 125-2, 125-3,made of a conductive material such as platinum, iridium,platinum-iridium alloys, and/or oxides thereof. The electrode ribbonsare individually bonded to an inside surface of an elastomeric bodyportion of the spiral electrodes 125-1, 125-2, 125-3 (FIG. 1C), whichmay comprise spiral loops of a multi-loop helical assembly. Leadassembly 122 may comprise three distinct lead wires or a triaxial cablethat are respectively coupled to one of the conductive electroderibbons. One suitable method of coupling the lead wires to theelectrodes 125-1, 125-2, 125-3 comprises a spacer assembly such as thatdisclosed in U.S. Pat. No. 5,531,778, although other known couplingmethods may be used.

The elastomeric body portion of each loop may be composed of siliconerubber or other biocompatible elastomeric compounds, and the fourth loop128 (which may have no electrode in some embodiments) acts as theanchoring tether for the electrode assembly 125.

In one embodiment, electrical pulse generator 110 may be programmed withan external computer 150 using programming software known in the art forstimulating neural structures, and a programming wand 155 to facilitateradio frequency (RF) communication between the external computer 150(FIG. 1A) and the implanted pulse generator 110. In one embodiment, wand155 and software permit wireless, non-invasive communication with thegenerator 110 after surgical implantation. Wand 155 may be powered byinternal batteries, and provided with a “power on” light to indicatesufficient power for communications. Another indicator light may beprovided to show that data transmission is occurring between the wandand the generator. In other embodiments, wand 155 may be omitted, e.g.,where communications occur in the 401-406 MHz bandwidth for MedicalImplant Communication Service (MICS band).

In some embodiments of the disclosure, a body data stream may beanalyzed to determine whether or not a seizure has occurred. Manydifferent body data streams and seizure detection indices have beenproposed for detecting epileptic seizures. Additional details on methodof detecting seizure from body data are provided in U.S. Pat. Nos.8,337,404 and 8,382,667, both issued in the name of the presentapplicant and both entitled, “Detecting, Quantifying, and/or ClassifyingSeizures Using Multimodal Data,” as well as in co-pending U.S. patentapplication Ser. No. 13/288,886, filed Nov. 3, 2011, each herebyincorporated by reference in its entirety herein. Seizure detectionbased on the patient's heart rate (as sensed by implanted or externalelectrodes), movement (as sensed by, e.g., a triaxial accelerometer),responsiveness, breathing, blood oxygen saturation, skinresistivity/conductivity, temperature, brain activity, and a number ofother body data streams are provided in the foregoing patents andco-pending applications.

In one embodiment, the present disclosure provides a method for treatinga patient with epilepsy in which a body data stream is analyzed using aseizure detection algorithm to determine whether or not the patient hashad an epileptic seizure. As used herein, the term “has had an epilepticseizure” includes instances in which a seizure onset has been detected,as well as instances in which the seizure onset has been detected andthe seizure is still ongoing (i.e., the seizure has not ended). If theanalysis results in a determination that the patient has not had anepileptic seizure, a signal generator may apply a first electricalsignal to a main trunk of a vagus nerve of the patient. If the analysisresults in a determination that the patient has had an epilepticseizure, the signal generator may apply a second electrical signal to acardiac branch of a vagus nerve of the patient. In some embodiments, theapplication of the first electrical signal to the main trunk isterminated, and only the second electrical signal to the cardiac branchis provided once a seizure is detected.

In alternative embodiments, both the first and second electrical signalsmay be applied to the main trunk and cardiac branch, respectively, ofthe vagus nerve in response to a determination that the patient has hada seizure (i.e., the first electrical signal continues to be applied tothe main trunk of the vagus nerve and the second signal is initiated).Where both the first and second electrical signals are provided, the twosignals may be provided sequentially, or in alternating fashion to themain trunk and the cardiac branch. In one embodiment, the first signalmay be provided to the main trunk by using one of the upper main trunkelectrode 125-1 or the lower main trunk electrode 125-3 as the cathodeand the cardiac branch electrode 125-2 as the anode, or by using both ofthe upper main trunk electrode and the lower main trunk electrode as thecathode and the anode. The second signal may be provided (e.g., byrapidly changing the polarity of the electrodes) by using the cardiacbranch electrode 125-2 as the cathode and a main trunk electrode 125-1or 125-3 as the anode.

In still other embodiments, the second electrical signal is applied tothe cardiac branch of the vagus nerve only if the analysis results in adetermination that the patient is having and/or has had an epilepticevent that is accompanied by an increase in heart rate, and the secondelectrical signal is used to lower the heart rate back towards a ratethat existed prior to the seizure onset. Without being bound by theory,the present inventors believe that slowing the heart rate at the onsetof seizures—particularly where the seizure is accompanied by an increasein heart rate—may improve the ability of VNS therapy to providecardio-protective benefits.

Prior patents describing vagus nerve stimulation as a medical therapyhave cautioned that undesired slowing of the heart rate may occur, andhave proposed various methods of avoiding such a slowing of the heartrate. In U.S. Pat. No. 6,341,236, it is suggested to sense heart rateduring delivery of VNS and if a slowing of the heart rate is detected,either suspending delivery of the VNS signal or pacing the heart using apacemaker. The present application discloses a VNS system that detectsepileptic seizures, particularly epileptic seizures accompanied by anincrease in heart rate, and intentionally applies an electrical signalto slow the heart rate in response to such a detection. In anotheraspect, the present application discloses VNS systems that provide afirst electrical signal to modulate only the brain during periods inwhich no seizure has been detected, and either 1) a second electricalsignal to modulate only the heart (to slow its rate) or 2) both a firstelectrical signal to the brain and a second electrical signal to theheart, in response to a detection of the onset of an epileptic seizure.These electrical signals may be delivered simultaneously, sequentially(e.g., delivery of stimulation to the brain precedes delivery ofstimulation to the heart or vice versa), or delivery of the first andsecond signals may be interspersed or interleaved.

The first electrode may be used as a cathode to provide an afferentfirst electrical signal to modulate the brain of the patient via maintrunk electrode 125-1. Electrode 125-1 may generate both afferent andefferent action potentials in vagus nerve 127. One or more of electrodes125-2 and 125-3 are used as anodes to complete the circuit. Where thisis the case, some of the action potentials may be blocked at theanode(s), with the result that the first electrical signal maypredominantly modulate the brain by afferent actions traveling towardthe brain, but may also modulate one or more other organs by efferentaction potentials traveling toward the heart and/or lower organs, to theextent that the efferent action potentials are not blocked by theanode(s).

The second electrode may be used as a cathode to provide an efferentsecond electrical signal to slow the heart rate of the patient viacardiac branch electrode 125-2. Either first electrode 125-1 or a thirdelectrode 125-3 (or can 121) may be used as an anode to complete thecircuit. In one embodiment, the first electrical signal may be appliedto the upper (127-1) or lower (127-3) main trunk of the vagus nerve inan open-loop manner according to programmed parameters including anoff-time and an on-time. The on-time and off-time together establish theduty cycle determining the fraction of time that the signal generatorapplies the first electrical. In one embodiment, the off-time may rangefrom 7 seconds to several hours or even longer, and the on-time mayrange from 5 seconds to 300 seconds. It should be noted that the dutycycle does not indicate when current is flowing through the circuit,which is determined from the on-time together with the pulse frequency(usually 10-200, Hz, and more commonly 20-30 Hz) and pulse width(typically 0.1-0.5 milliseconds). The first electrical signal may alsobe defined by a current magnitude (e.g., 0.25-3.5 milliamps), andpossibly other parameters (e.g., pulse width, and whether or not acurrent ramp-up and/or ramp-down is provided, a frequency, and a pulsewidth.

In one embodiment, a seizure detection may result in both applying thefirst electrical signal to provide stimulation to the brain in closeproximity to a seizure detection (which may interrupt or terminate theseizure), as well as application of the second electrical signal whichmay slow the heart, thus exerting a cardio-protective effect. In aparticular embodiment, the second electrical signal is applied only inresponse to a seizure detection that is characterized by (or accompaniedor associated with) an increase in heart rate, and is not applied inresponse to seizure detections that are not characterized by an increasein heart rate. In this manner, the second electrical signal may helpinterrupt the seizure by restoring the heart to a pre-seizure baselineheart rate when the patient experiences ictal tachycardia (elevatedheart rate during the seizure), while leaving the heart rate unchangedif the seizure has no significant effect on heart rate.

In still further embodiments, additional logical conditions may beestablished to control when the second electrical signal is applied tolower the patient's heart rate following a seizure detection. In oneembodiment, the second electrical signal is applied only if themagnitude of the ictal tachycardia rises above a defined level. In oneembodiment, the second electrical signal is applied to the cardiacbranch only if the heart rate increases by a threshold amount above thepre-ictal baseline heart rate (e.g., more than 20 beats per minute abovethe baseline rate). In another embodiment, the second electrical signalis applied to the cardiac branch only if the heart rate exceeds anabsolute heart rate threshold (e.g., 100 beats per minute, 120 beats perminute, or other programmable threshold). In a further embodiment, aduration constraint may be added to one or both of the heart rateincrease or absolute heart rate thresholds, such as a requirement thatthe heart rate exceed the baseline rate by 20 beats per minute for morethan 10 seconds, or exceed 110 beats per minute for more than 10seconds, before the second electrical signal is applied to the cardiacbranch in response to a seizure detection.

In another embodiment, the heart rate sensor continues to monitor thepatient's heart rate during and/or after application of the secondelectrical signal, and the second electrical signal is interrupted orterminated if the patient's heart rate is reduced below a low heart ratethreshold, which may be the baseline heart rate that the patientexperienced prior to the seizure, or a rate lower or higher than thebaseline pre-ictal heart rate. The low rate threshold may provide ameasure of safety to avoid undesired events such as bradycardia and/orsyncope.

In yet another embodiment, heart rate sensor 130 may continue to monitorheart rate and/or kinetic sensor 140 may continue to monitor bodymovement in response to applying the second electrical signal, and thesecond electrical signal may be modified (e.g., by changing one or moreparameters such as pulse frequency, or by interrupting and re-initiatingthe application of the second electrical signal to the cardiac branch ofthe vagus nerve) to control the heart rate below an upper heart ratethreshold and/or body movement exceeds one or more movement thresholds.For example, the frequency or duration of the second electrical signalapplied to the cardiac branch of the vagus nerve may be continuouslymodified based the instantaneous heart rate as monitored during thecourse of a seizure to control what would otherwise be an episode ofictal tachycardia below an upper heart rate threshold. In one exemplaryembodiment, the second electrical signal may be programmed to provide a30-second pulse burst at 30 Hz, with the pulses having a pulse width of0.25 milliseconds and a current of 1.5 milliamps. If, at the end of the30 second burst, the heart rate remains above 120 beats per minute, andis continuing to rise, the burst may be extended to 1 minute instead of30 seconds, the frequency may be increased to 50 Hz, the pulse width maybe increased to 350 milliseconds, or combinations of the foregoing. Instill further embodiments, additional therapies (e.g., oxygen delivery,drug delivery, cooling therapies, etc.) may be provided to the patientif the body data (heart rate, kinetic activity, etc.) indicates that thepatient's seizure is not under control or terminated.

Abnormalities or changes in EKG morphology or rhythm relative to aninterictal morphology or rhythm may also trigger delivery of current tothe heart via the trunks of vagi or its cardiac rami. In otherembodiments, pharmacological agents such as beta-blockers may beautomatically released into a patient's blood stream in response to thedetection of abnormal heart activity during or between seizures.

In one embodiment, the first electrical signal and the second electricalsignal are substantially identical. In another embodiment, the firstelectrical signal may vary from the second electrical signal in terms ofone or more of pulse width, number of pulses, amplitude, frequency,inter-pulse-interval, stimulation on-time, and stimulation off-time,among other parameters and degree, rate or type of charge balancing.

The number of pulses applied to the main trunk or cardiac branch,respectively, before changing the polarity of the first and secondelectrodes need not be one. Thus, two or more pulses may be applied tothe main trunk before applying pulses to the cardiac branch of the vagusnerve. More generally, the first and second signals can be independentof one another and applied according to timing and programmingparameters controlled by the controller 210 and stimulation unit 220.

In one embodiment, one or more pulse bursts of the first electricalsignal are applied to the main trunk of the vagus nerve in response to adetected seizure before applying one or more bursts of the secondelectrical signal to the cardiac branch. In another embodiment, thefirst and second signals are interleaved on a pulse-by-pulse basis underthe control of the controller 210 and stimulation unit 220.

Typically, VNS can be performed with pulse frequency of 20-30 Hz(resulting in a number of pulses per burst of 140-1800, at a burstduration from 7-60 sec). In one embodiment, at least one of the firstelectrical signal and the second electrical signal comprises amicroburst signal. Microburst neurostimulation is discussed by U.S. Ser.No. 11/693,451, filed Mar. 2, 2007 and published as United States patentPublication No. 20070233193, and incorporated herein by reference in itsentirety. In one embodiment, at least one of the first electricalsignal, the second electrical signal, and the third electrical signal ischaracterized by having a number of pulses per microburst from 2 pulsesto about 25 pulses, an interpulse interval of about 2 msec to about 50msec, an interburst period of at least 100 msec, and a microburstduration of less than about 1 sec.

Cranial nerves such as the vagus nerve include different types of nervefibers, such as A-fibers, B-fibers and C-fibers. The different fibertypes propagate action potentials at different velocities. Each nervefiber is directional—that is, endogenous or natural action potentialscan generally propagate action potentials in only one direction (e.g.,afferently to the brain or efferently to the heart and/or viscera). Thatdirection is referred to as the orthodromic direction. Exogenousstimulation (e.g., by electrical pulses) may induce action potentials inboth the orthodromic direction as well as the antidromic direction.Depending upon the desired effects of stimulation (e.g., afferentmodulation of the brain, efferent modulation of the heart, etc.) certainmeasures (e.g., cooling, pressure, etc.) may be taken to blockpropagation in either the efferent or the afferent direction. It isbelieved that the anode may block at least some action potentialstraveling to it from the cathode. For example, referring to FIG. 1, bothafferent and efferent action potentials may be generated in an uppermain trunk of vagus nerve 127-1 by applying a pulse to the nerve usingupper main trunk electrode 125-1 as a cathode. Action potentialsgenerated at upper main trunk electrode 125-1 and traveling toward theheart on cardiac branch 127-2 may be blocked by cardiac branch anode125-2. Action potentials traveling from the upper main trunk 127-1 tothe lower organs in lower main trunk 127-3 may be either blocked (byusing lower main trunk electrode 125-3 as an anode either with orinstead of cardiac branch electrode 125-2) or allowed to travel to thelower organs (by not using electrode structure 125-3 as an electrode).

Action potentials may be generated and allowed to travel to the heart bymaking the electrode 125-2 the cathode. If cardiac branch electrode125-2 is used as a cathode, action potentials will reach the heart inlarge numbers, while action potentials traveling afferently toward thebrain may be blocked in the upper trunk if upper electrode 125-1 is madethe anode.

In a further embodiment of the disclosure, rapid changes in electrodepolarity may be used to generate action potentials to collision blockaction potentials propagating in the opposite direction. To generalize,in some embodiments, the vagus nerve can be selectively stimulated topropagate action potentials either afferently (i.e., to the brain) orefferently (i.e., to the heart and/or lower organs/viscerae).

Turning now to FIG. 2, a block diagram depiction of an implantablemedical device, in accordance with one illustrative embodiment of thepresent disclosure is illustrated. The IMD 200 may be coupled to variouselectrodes 125 and/or 127 via lead(s) 122 (FIGS. 1A, 1C). First andsecond electrical signals used for therapy may be transmitted from theIMD 200 to target areas of the patient's body, specifically to variouselectrodes associated with the leads 122. Stimulation signals from theIMD 200 may be transmitted via the leads 122 to stimulation electrodes(electrodes that apply the therapeutic electrical signal to the targettissue) associated with the electrode assembly 125, e.g., 125-1, 125-2,125-3 (FIG. 1A).

The IMD 200 may comprise a controller 210 capable of controlling variousaspects of the operation of the IMD 200. The controller 210 is capableof receiving internal data and/or external data and controlling thegeneration and delivery of a stimulation signal to target tissues of thepatient's body. For example, the controller 210 may receive manualinstructions from an operator externally, may perform stimulation basedon internal calculations and programming, and may receive and/or processsensor data received from one or more body data sensors such aselectrodes 125-1, 125-2, 125-3, or heart rate sensor 130. The controller210 is capable of affecting substantially all functions of the IMD 200.

The controller 210 may comprise various components, such as a processor215, a memory 217, etc. The processor 215 may comprise one or more microcontrollers, microprocessors, etc., that are capable of executing avariety of software components. The processor may receive, pre-conditionand/or condition sensor signals, and may control operations of othercomponents of the IMD 200, such as stimulation unit 220, seizuredetection module 240, logic unit 250, communication unit, 260, andelectrode polarity reversal unit 280. The memory 217 may comprisevarious memory portions, where a number of types of data (e.g., internaldata, external data instructions, software codes, status data,diagnostic data, etc.) may be stored. The memory 217 may store varioustables or other database content that could be used by the IMD 200 toimplement the override of normal operations. The memory 217 may compriserandom access memory (RAM) dynamic random access memory (DRAM),electrically erasable programmable read-only memory (EEPROM), flashmemory, etc.

The IMD 200 may also comprise a stimulation unit 220. The stimulationunit 220 is capable of generating and delivering a variety of electricalsignal therapy signals to one or more electrodes via leads. Thestimulation unit 220 is capable of delivering a programmed, firstelectrical signal to the leads 122 coupled to the IMD 200. Theelectrical signal may be delivered to the leads 122 by the stimulationunit 220 based upon instructions from the controller 210. Thestimulation unit 220 may comprise various types of circuitry, such asstimulation signal generators, impedance control circuitry to controlthe impedance “seen” by the leads, and other circuitry that receivesinstructions relating to the type of stimulation to be performed.

Signals from sensors (electrodes that are used to sense one or more bodyparameters such as temperature, heart rate, brain activity, etc.) may beprovided to the IMD 200. The body signal data from the sensors may beused by a seizure detection algorithm embedded or processed in seizuredetection module 240 to determine whether or not the patient is havingand/or has had an epileptic seizure. The seizure detection algorithm maycomprise hardware, software, firmware or combinations thereof, and mayoperate under the control of the controller 210. Although not shown,additional signal conditioning and filter elements (e.g., amplifiers,D/A converters, etc., may be used to appropriately condition the signalfor use by the seizure detection module 240. Sensors such as heartsensor 130 and kinetic sensor 140 may be used to detect seizures, alongwith other autonomic, neurologic, or other body data.

The IMD 200 may also comprise an electrode polarity reversal unit 280.The electrode polarity reversal unit 280 is capable of reversing thepolarity of electrodes (125-1, 125-2, 125-3) associated with theelectrode assembly 125. The electrode polarity reversal unit 280 isshown in more detail in FIG. 3. In preferred embodiments, the electrodepolarity reversal unit is capable of reversing electrode polarityrapidly, i.e., in about 10 microseconds or less, and in any event at asufficiently rapid rate to permit electrode polarities to be changedbetween adjacent pulses in a pulsed electrical signal.

The IMD 200 may also comprise a power supply 230. The power supply 230may comprise a battery, voltage regulators, capacitors, etc., to providepower for the operation of the IMD 200, including delivering thestimulation signal. The power supply 230 comprises a power-sourcebattery that in some embodiments may be rechargeable. In otherembodiments, a non-rechargeable battery may be used. The power supply230 provides power for the operation of the IMD 200, includingelectronic operations and the stimulation function. The power supply 230may comprise a lithium/thionyl chloride cell or a lithium/carbonmonofluoride (LiCFx) cell. Other battery types known in the art ofimplantable medical devices may also be used.

The IMD 200 also comprises a communication unit 260 capable offacilitating communications between the IMD 200 and various devices. Inparticular, the communication unit 260 is capable of providingtransmission and reception of electronic signals to and from an externalunit 270. The external unit 270 may be a device that is capable ofprogramming various modules and stimulation parameters of the IMD 200.In one embodiment, the external unit 270 comprises a computer systemthat is capable of executing a data-acquisition program. The externalunit 270 may be controlled by a healthcare provider, such as aphysician, at a base station in, for example, a doctor's office. Theexternal unit 270 may be a computer, preferably a handheld computer orPDA, but may alternatively comprise any other device that is capable ofelectronic communications and programming The external unit 270 maydownload various parameters and program software into the IMD 200 forprogramming the operation of the implantable device. The external unit270 may also receive and upload various status conditions and other datafrom the IMD 200. The communication unit 260 may be hardware, software,firmware, and/or any combination thereof. Communications between theexternal unit 270 and the communication unit 260 may occur via awireless or other type of communication, illustrated generally by line275 in FIG. 2.

In one embodiment, the communication unit 260 can transmit a log ofstimulation data and/or seizure detection data to the patient, aphysician, or another party.

In one embodiment, a method of treating an epileptic seizure is providedthat involves providing simultaneously both a first electrical signal toa main trunk of a vagus nerve and a second electrical signal to acardiac branch of the vagus nerve. As used herein “simultaneously”refers to the on-time of the first and second signals, and does notrequire that individual pulses of the first signal and the second signalbe simultaneously applied to target tissue. The timing of pulses for thefirst electrical signal and the second electrical signal may bedetermined by controller 210 in conjunction with stimulation unit 220.Where active charge-balancing is used, it may be possible to use theactive charge-balancing phase of pulses of the first electrical signalas the stimulation phase of the second electrical signal by selecting acurrent magnitude of the cathode in the charge-balancing phase(typically a second electrode, which may be the anode of the initialstimulation phase) that is sufficient to generate action potentials innerve fibers of the target tissue. Controller 210 may in someembodiments provide simultaneous delivery of first and second electricalsignals by interleaving pulses for each of the first and secondelectrical signals based upon the programmed timing of pulses for eachsignal and the appropriate polarity of each of first and secondelectrodes 125-1 and 125-2. In some embodiments, additional electrodesmay be used to minimize the induction of action potentials to the heartor the brain provided by the first electrical signal or the secondelectrical signal. This may be accomplished, in one embodiment, by usingan anode located on either the upper main trunk or the cardiac branch toblock impulse conduction to the heart or brain from the cathode, or byproviding dedicated electrode pairs on both the main trunk and cardiacbranches (FIGS. 1D, 1E). When beneficial, steps to avoid collisions ofactions potentials travelling in opposite directions may be implemented,while steps to promote collisions may be taken when clinicallyindicated. In some embodiments, the method further includes sensing acardiac signal and a kinetic signal of the patient, and detecting aseizure event with a seizure detection algorithm.

In one embodiment, a first electrical signal is applied to a main trunkof a vagus nerve and a second electrical signal is simultaneouslyapplied to a cardiac branch of a vagus nerve. A pulse of the firstelectrical signal is generated with the electrical signal generator 110and applied to the main trunk of the vagus nerve using a first electrode(e.g., 125-1, 125-1 a) as a cathode and a second electrode (e.g., 125-1b, 125-3, or 125-2) as an anode. The method includes sensing a cardiacsignal and a kinetic signal of the patient, and detecting a seizureevent with a seizure detection algorithm. A pulse of the secondelectrical signal (having the appropriate pulse width and current) isgenerated and applied (under appropriate timing control by controller110 and stimulation unit 220) to the cardiac branch of the vagus nerveusing a second electrode (e.g., 125-2, 125-2 a) as a cathode and anotherelectrode (e.g., 125-3, 125-1, 125-2 b) as an anode. Another pulse ofthe first electrical signal may thereafter be generated and applied tothe main trunk under timing and parameter control of controller 210 andstimulation unit 220. By appropriate selection of cathodes and anodes,the first and second electrical signals may be interleaved and providedsimultaneously to the main trunk and cardiac branches of the vagusnerve. In some embodiments, the number of electrodes may be minimized byprovided a polarity reversal unit that may rapidly change the polarityof particular electrodes to allow their use in delivering both the firstand second signals.

The IMD 200 is capable of delivering stimulation that can be contingent,periodic, random, coded, and/or patterned. The stimulation signals maycomprise an electrical stimulation frequency of approximately 0.1 to10,000 Hz. The stimulation signals may comprise a pulse width in therange of approximately 1-2000 micro-seconds. The stimulation signals maycomprise current amplitude in the range of approximately 0.1 mA to 10mA. Appropriate precautions may be taken to avoid delivering injuriouscurrent densities to target neural tissues, e.g., by selecting current,voltage, frequency, pulse width, on-time and off-time parameters tomaintain current density below thresholds for damaging tissues.

The IMD 200 may also comprise a magnetic field detection unit 290. Themagnetic field detection unit 290 is capable of detecting magneticand/or electromagnetic fields of a predetermined magnitude. Whether themagnetic field results from a magnet placed proximate to the IMD 200, orwhether it results from a substantial magnetic field encompassing anarea, the magnetic field detection unit 290 is capable of informing theIMD of the existence of a magnetic field. The changeable electrodepolarity stimulation described herein may be activated, deactivated, oralternatively activated or deactivated using a magnetic input.

The magnetic field detection unit 290 may comprise various sensors, suchas a Reed Switch circuitry, a Hall Effect sensor circuitry, and/or thelike. The magnetic field detection unit 290 may also comprise variousregisters and/or data transceiver circuits that are capable of sendingsignals that are indicative of various magnetic fields, the time periodof such fields, etc. In this manner, the magnetic field detection unit290 is capable of detecting whether the detected magnetic field relatesto an input to implement a particular first or second electrical signal(or both) for application to the main trunk of cardiac branches,respectively, of the vagus nerve.

One or more of the blocks illustrated in the block diagram of the IMD200 in FIG. 2, may comprise hardware units, software units, firmwareunits, or any combination thereof. Additionally, one or more blocksillustrated in FIG. 2 may be combined with other blocks, which mayrepresent circuit hardware units, software algorithms, etc.Additionally, one or more of the circuitry and/or software unitsassociated with the various blocks illustrated in FIG. 2 may be combinedinto a programmable device, such as a field programmable gate array, anASIC device, etc.

FIG. 3 shows in greater detail an electrode polarity reversal unit 280(FIG. 2) in one embodiment. The electrode polarity reversal unit 280comprises an electrode configuration switching unit 340, which includesa switching controller 345. The switching controller 345 transmitssignals to one or more switches, generically, n switches 330(1), 330(2),. . . 330(n) which effect the switching of the configuration of two ormore electrodes, generically, n electrodes 125(1), 125(2), . . . 125(n).Although FIG. 3 shows equal numbers of switches 330 and electrodes 125,persons of skill in the art having the benefit of the present disclosurewill understand that the number of switches 330 and their connectionswith the various electrodes 125 can be varied as a matter of routineoptimization. A switching timing unit 333 can signal to the electrodeconfiguration switching unit 340 that a desired time for switching theelectrode configuration has been reached.

Instructions for implementing two or more stimulation regimens, whichmay include at least one open-loop electrical signal and at least oneclosed-loop electrical signal, may be stored in the IMD 200. Thesestimulation signals may include data relating to the type of stimulationsignal to be implemented. In one embodiment, an open-loop signal may beapplied to generate action potentials for modulating the brain of thepatient, and a closed-loop signal may be applied to generate eitheraction potentials for slowing the heart rate of the patient, or bothaction potentials to modulate the brain of the patient as well as actionpotentials for slowing the heart rate of the patient. In someembodiments, the open-loop and closed-loop signals may be provided todifferent target portions of a vagus nerve of the patient by switchingthe polarity of two or more electrodes using an electrode polarityreversal unit as described in FIG. 3 above. In alternative embodiments,additional electrodes may be provided to generate each of the open-loopand closed-loop signals without electrode switching.

In one embodiment, a first open-loop mode of stimulation may be used toprovide an electrical signal to a vagus nerve using a first electrode asa cathode on a main trunk (e.g., 127-1 or 127-3 using electrodes 125-1or 125-3, respectively) of a vagus nerve, and a second electrode as ananode on either a main trunk (e.g., electrode 125-3, when electrode125-1 is used as a cathode) or cardiac branch (e.g., electrode 125-2) ofa vagus nerve. The first open-loop signal may include a programmedon-time and off-time during which electrical pulses are applied (theon-time) and not-applied (the off-time) in a repeating sequence to thevagus nerve.

A second, closed-loop signal may be provided in response to a detectedevent (such as an epileptic seizure, particularly when accompanied by anincrease in the patient's heart rate) using a different electrodeconfiguration than the first, open-loop signal. In one embodiment, thesecond, closed-loop signal is applied to a cardiac branch using thesecond electrode 125-2 as a cathode and the first electrode on the maintrunk (e.g., 125-1 or 125-3) as an anode. The second, closed-loop signalmay involve generating efferent action potentials on the cardiac branchof the vagus nerve to slow the heart rate. In some embodiments, thefirst, open-loop signal may be interrupted/suspended in response to thedetected event, and only the second, closed-loop signal is applied tothe nerve. In other embodiments, the first, open loop signal may not beinterrupted when the event is detected, and both the first, open-loopsignal and the second, closed-loop signal are applied to the vagusnerve. In another embodiment, a third, closed-loop signal may also beprovided in response to the detected event. The third, closed-loopsignal may involve an electrical signal using the same electrodeconfiguration as the first, open-loop electrical signal, but may providea different electrical signal to the main trunk of the vagus nerve thaneither the first, open-loop signal or the second, closed-loop signal.The first, open-loop signal may be interrupted, terminated or suspendedin response to the detected event, and the third, closed-loop signal maybe applied to the nerve either alone or with the second, closed-loopsignal. In some embodiments, both the second and third closed-loopsignals may be provided in response to a detected epileptic seizure byrapidly changing the polarity of the first (125-1) and second (125-2)electrodes from cathode to anode and back, as pulses are provided aspart of the second and third electrical signals, respectively. In oneembodiment, the third electrical signal may involve modulating the brainby using a main trunk electrode (e.g., upper main trunk electrode 125-1)as a cathode and another electrode (e.g., cardiac branch electrode 125-2or lower main trunk electrode 125-3) as an anode. The third electricalsignal may comprise, for example, a signal that is similar to the firstelectrical signal but which provides a higher electrical current thanthe first electrical signal, and for a longer duration than the firstsignal or for a duration that is adaptively determined based upon asensed body signal (in contrast, for example, to a fixed duration of thefirst electrical signal determined by a programmed on-time). By rapidlychanging polarity of the electrodes, pulses for each of the second andthird electrical signals may be provided such that the second and thirdsignals are provided simultaneously to the cardiac branch and main trunkof the vagus nerve. In other embodiments, the first, second and thirdelectrical signals may be provided sequentially rather thansimultaneously.

In some embodiments, one or more of the first, second and thirdelectrical signals may comprise a microburst signal, as described morefully in U.S. patent application Ser. Nos. 11/693,421, 11/693,451, and11/693,499, each filed Mar. 29, 2007 and each hereby incorporated byreference herein in their entirety.

In one embodiment, each of a plurality of stimulation regimens mayrespectively relate to a particular disorder, or to particular eventscharacterizing the disorder. For example, different electrical signalsmay be provided to one or both of the main trunk and cardiac branches ofthe vagus nerve depending upon what effects accompany the seizure. In aparticular embodiment, a first open-loop signal may be provided to thepatient in the absence of a seizure detection, while a second,closed-loop signal may be provided when a seizure is detected based on afirst type of body movement of the patient as detected by, e.g., anaccelerometer, a third, closed-loop signal may be provided when theseizure is characterized by a second type of body movement, a fourth,closed-loop signal may be provided when the seizure is characterized byan increase in heart rate, a fifth, closed-loop signal may be providedwhen the seizure is characterized by a decrease in heart rate, and soon. More generally, stimulation of particular branches or main trunktargets of a vagus nerve may be provided based upon different bodysignals of the patient. In some embodiments, additional therapies may beprovided based on different events that accompany the seizure, e.g.,stimulation of a trigeminal nerve or providing a drug therapy to thepatient through a drug pump. In one embodiment, different regimensrelating to the same disorder may be implemented to accommodateimprovements or regressions in the patient's present condition relativeto his or her condition at previous times. By providing flexibility inelectrode configurations nearly instantaneously, the present disclosuregreatly expands the range of adjustments that may be made to respond tochanges in the patient's underlying medical condition.

The switching controller 345 may be a processor that is capable ofreceiving data relating to the stimulation regimens. In an alternativeembodiment, the switching controller may be a software or a firmwaremodule. Based upon the particulars of the stimulation regimens, theswitching timing unit 333 may provide timing data to the switchingcontroller 345. The first through nth switches 330(1-n) may beelectrical devices, electro-mechanical devices, and/or solid statedevices (e.g., transistors).

FIG. 4 shows one embodiment of a method of treating a patient havingepilepsy according to the present disclosure. In this embodiment, afirst electrode is coupled to a main trunk of a vagus nerve of thepatient (410) and a second electrode is coupled to a cardiac branch ofthe vagus nerve (420). An electrical signal generator is coupled to thefirst and second electrodes (430).

The method further involves receiving at least one body data stream ofthe patient (440). The data may be sensed by a sensor such as heart ratesensor 130 (FIG. 1A) or a sensor that is an integral part of, or coupledto, an IMD 200 (FIG. 2) such as electrical pulse generator 110 (FIG.1A), and the IMD may also receive the data from the sensor. The at leastone body data stream is then analyzed using a seizure detectionalgorithm (450), and the seizure detection algorithm determines whetheror not the patient is having and/or has had an epileptic seizure (460).

If the algorithm indicates that the patient is not having and/or has nothad an epileptic seizure, the method comprises applying a firstelectrical signal from the electrical signal generator to the main trunkof a vagus nerve using the first electrode as a cathode (470). In oneembodiment, applying the first electrical signal comprises continuing toapply a programmed, open-loop electrical signal periodically to the maintrunk of the vagus nerve according a programmed on-time and off-time.

If the algorithm indicates that the patient is having and/or has had anepileptic seizure, the method comprises applying a second electricalsignal from the electrical signal generator to the cardiac branch of thevagus nerve using the second electrode as a cathode (480). Dependingupon which electrical signal (first or second) is applied, the methodmay involve changing the polarity of one or both of the first electrodeand the second electrode. In one embodiment, the method may comprisesuspending the first electrical and applying the second electricalsignal. In one embodiment, the method comprises continuing to receive atleast one body data stream of the patient at 440 after determiningwhether or not the patient is having and/or has had an epilepticseizure.

In an alternative embodiment, if the seizure detection algorithmindicates that the patient is having and/or has had an epilepticseizure, both the first electrical signal and the second electricalsignal are applied to the main trunk and cardiac branches of a vagusnerve of the patient, respectively, at step 480. In a specificimplementation of the alternative embodiment, pulses of the first andsecond electrical signal are applied to the main trunk and cardiacbranch of the vagus nerve under the control of controller 210 by rapidlychanging the polarity of the first and second electrodes using theelectrode polarity reversal unit 280 to apply the first electricalsignal to the main trunk using the first electrode as a cathode and thesecond electrode as an anode, changing the polarity of the first andsecond electrodes, and applying the second electrical signal to thecardiac branch using the second electrode as a cathode and the firstelectrode as an anode. Additional pulses for each signal may besimilarly applied by rapidly changing the polarity of the electrodes.

In some embodiments, the first electrical signal and the secondelectrical signal are applied unilaterally, i.e., to a vagal main trunkand a cardiac branch on the same side of the body. In other embodiments,the first and second electrical signals are applied bilaterally, i.e.,the second electrical signal is applied to a cardiac branch on theopposite side of the body from the main vagal trunk to which the firstelectrical signal is applied. In one embodiment, the first electricalsignal is applied to a left main trunk to minimize cardiac effects ofthe first electrical signal, and the second electrical signal is appliedto a right cardiac branch, which modulates the sinoatrial node of theheart to maximize cardiac effects of the second electrical signal.

In alternative embodiments, both the first electrode and the secondelectrode may be coupled to a cardiac branch of a vagus nerve, with thefirst electrode (e.g., anode) being proximal to the brain relative tothe second electrode, and the second electrode (e.g., cathode) beingproximal to the heart relative to the first electrode.

FIG. 5 is a flow diagram of another method of treating a patient havingepilepsy according to the present disclosure. A sensor is used to sensea cardiac signal and a kinetic signal of the patient (540). In aparticular embodiment, the cardiac sensor may comprise an electrode pairfor sensing an ECG (electrocardiogram) or heart beat signal, and thekinetic signal may comprise a triaxial accelerometer to detect motion ofat least a portion of the patient's body. The method further comprisesanalyzing at least one of the cardiac signal and the kinetic signalusing seizure detection algorithm (550), and the output of the algorithmis used to determine whether at least one of the cardiac signal and thekinetic signal indicate that the patient is having and/or has had anepileptic seizure (560).

If the patient is not having and/or has not had an epileptic seizure,the method comprises applying a first electrical signal to a main trunkof a vagus nerve of the patient using a first electrode, coupled to themain trunk, as a cathode (580). In one embodiment, the first electricalsignal is an open-loop electrical signal having an on-time and off-time.

If the patient is having and/or has had an epileptic seizure, adetermination is made whether the seizure is characterized by anincrease in the patient's heart rate (570). If the seizure is notcharacterized by an increase in the patient's heart rate, the methodcomprises applying the first electrical signal to the main trunk of avagus nerve using the first electrode as a cathode (580). In oneembodiment, the cathode comprises an upper main trunk electrode 125-1and the anode is selected from a cardiac branch electrode 125-2 and alower main trunk electrode 125-3. Conversely, if the seizure ischaracterized by an increase in the patient's heart rate, the methodcomprises applying a second electrical signal to a cardiac branch of avagus nerve of the patient using a second electrode, coupled to thecardiac branch, as a cathode (590). The anode is an upper main trunkelectrode 125-1 or a lower main trunk electrode 125-3. In oneembodiment, the method may comprise suspending the first electrical andapplying the second electrical signal.

The method then continues the sensing of the cardiac and kinetic signalsof the patient (540) and resumes the method as outlined in FIG. 5.

FIG. 6 is a flow diagram of a further method of treating a patienthaving epilepsy according to the present disclosure. The method includesapplying a first, open-loop electrical signal to a main trunk of a vagusnerve (610). The open-loop signal is characterized by an off-time inwhich electrical pulses are applied to the nerve, and an off-time inwhich electrical pulses are not applied to the nerve.

A sensor is used to sense at least one body signal of the patient (620),and a determination is made whether the at least one body signalindicates that the patient is having and/or has had an epileptic seizure(630). If the patient is not having and/or has not had a seizure, themethod continues applying the first, open-loop electrical signal to amain trunk of a vagus nerve (610). If the patient is having and/or hashad an epileptic seizure, a determination is made whether the seizure ischaracterized by an increase in the patient's heart rate (640). In oneembodiment, the increase in heart rate is measured from a baseline heartrate existing prior to the seizure, e.g., a median heart rate for aprior period such as the 300 beats prior to the detection of the seizureevent, or the 5 minutes prior to the detection of the seizure.

If the seizure is not characterized by an increase in the patient'sheart rate, the method comprises applying a second, closed-loopelectrical signal to the main trunk of the vagus nerve 650). In oneembodiment, the second, closed-loop electrical signal is the same signalas the open-loop electrical signal, except that the second signal (asdefined, e.g., by a current intensity, a pulse frequency, a pulse widthand an on-time) is applied at a time different from the programmedtiming of the first electrical signal. For example, if the firstelectrical signal comprises an on-time of 30 seconds and an off-time of5 minutes, but a seizure is detected 1 minute after the end of aprogrammed on-time, the second electrical signal may comprise applying a30 second pulse burst at the same current intensity, frequency, andpulse width as the first signal, but four minutes earlier than wouldhave occurred absent the detected seizure. In another embodiment, thesecond, closed-loop electrical signal is a different signal than thefirst, open-loop electrical signal, and the method may also comprisesuspending the first electrical before applying the second electricalsignal. For example, the second, closed-loop electrical signal maycomprise a higher current intensity, frequency, pulse width and/oron-time than the first, open-loop electrical signal, and may notcomprise an off-time (e.g., the second electrical signal may be appliedfor a predetermined duration independent of the on-time of the first,open-loop electrical signal, such as a fixed duration of 1 minute, ormay continue for as long as the body signal indicates the presence ofthe seizure event).

Returning to FIG. 6, if the seizure is characterized by an increase inthe patient's heart rate, the method comprises applying a third,closed-loop electrical signal to a cardiac branch of a vagus nerve toreduce the patient's heart rate (660). The method may comprisesuspending the first electrical as well as applying the third,closed-loop electrical signal. In one embodiment of the disclosure, eachof the first, open-loop electrical signal, the second, closed-loopelectrical signal, and the third, closed-loop electrical signal areapplied unilaterally (i.e., to vagus nerve structures on the same sideof the body) to the main trunk and cardiac branch of the vagus nerve.For example, the first, open-loop electrical signal and the second,closed-loop electrical signal may be applied to a left main trunk of thepatient's cervical vagus nerve, and the third, closed-loop electricalsignal may be applied to the left cardiac branch of the vagus nerve.Similarly, the first, second and third electrical signals may all beapplied to the right vagus nerve of the patient. In alternativeembodiments, one or more of the first, second and third electricalsignals may be applied bilaterally, i.e., one of the first, second andthird electrical signals is applied to a vagal structure on the oppositeside of the body from the other two signals. For example, in aparticular embodiment the first, open-loop signal and the second,closed-loop signal may be applied to a left main trunk of the patient'scervical vagus nerve, and the third, closed-loop electrical signal maybe applied to a right cardiac branch of the patient's vagus nerve.Because the right cardiac branch modulates the sinoatrial node of thepatient's heart, which is the heart's “natural pacemaker,” the thirdelectrical signal may have more pronounced effect in reducing thepatient's heart rate if applied to the right cardiac branch.

After applying one of the second (650) and third (660) electricalsignals to a vagus nerve of the patient, the method then continuessensing at least one body signal of the patient (620) and resumes themethod as outlined in FIG. 6.

In the methods depicted in FIGS. 4-6, one or more of the parametersdefining the first, second, and third electrical signals (e.g., numberof pulses, pulse frequency, pulse width, On time, Off time, interpulseinterval, number of pulses per burst, or interburst interval, amongothers) can be changed by a healthcare provided using a programmer 150.

FIG. 7 is a flow diagram of a method of treating patients havingseizures accompanied by increased heart rate. In one embodiment,tachycardia is defined as a neurogenic increase in heart rate, that is,an elevation in heart rate that occurs in the absence of motor activityor that if associated with motor activity, the magnitude of the increasein heart rate is larger than that caused by motor activity alone. In oneembodiment, a body signal is acquired (710). The body signal maycomprise one or more body signals that may be altered, changed orinfluenced by an epileptic seizure. As non-limiting examples, the bodysignal may comprise one or more of a cardiac signal such as heart rate,heart rate variability, or EKG complex morphology, a kinetic signal suchas an accelerometer signal, a postural signal or body position signal),blood pressure, blood oxygen concentration, skin resistivity orconductivity, pupil dilation, eye movement, EEG, reaction time or otherbody signals. The body signal may be a real-time signal or a storedsignal for delayed or later analysis. It may be acquired, for example,from a sensor element (e.g., coupled to a processor), from a storagedevice in which the signal data is stored.

The method further comprises determining whether or not the patient ishaving and/or has had a seizure accompanied by an increase in heart rate(720). In one embodiment, the method comprises a seizure detectionalgorithm that analyzes the acquired body signal data and determineswhether or not a seizure has occurred. In a particular embodiment, themethod comprises an algorithm that analyzes one or more of a cardiacsignal, a kinetic signal, a cognitive signal, blood pressure, bloodoxygen concentration, skin resistivity or conductivity, pupil dilation,and eye movement to identify changes in the one or more signals thatindicate a seizure has occurred. The method may comprise an outputsignal or data flag that may be asserted or set when the detectionalgorithm determines from the body signal(s) that the patient is havingand/or has had a seizure.

The method also comprises determining (720) whether or not the seizureis accompanied by an increase in heart rate. In one embodiment, the bodydata signal comprises a heartbeat signal that may be analyzed todetermine heart rate. In some embodiments, the heart beat signal may beused by the seizure detection algorithm to determine whether a seizurehas occurred, while in other embodiments seizures are not detected usingheart rate. Regardless of how the seizure is detected, however, themethod of FIG. 7 comprises determining whether a detected seizure eventis accompanied by an increase in heart rate. The increase may bedetermined in a variety of ways, such as by an increase in aninstantaneous heart rate above a reference heart rate (which may be apredetermined interictal value such as 72 beats per minute (bpm), or areal-time measure of central tendency for a time window, such as a 5minute median or moving average heart rate). Additional details aboutidentifying increases in heart rate in the context of epileptic seizuresare provided in U.S. Pat. Nos. 5,928,272, 6,341,236, 6,587,727,6,671,556, 6,961,618, 6,920,357, 7,457,665, as well as U.S. patentapplication Ser. Nos. 12/770,562, 12/771,727, 12/771,783, 12/884,051,12/886,419, 12/896,525, 13/098,262, and 13/288,886, each of which ishereby incorporated by reference in its entirety herein.

If the body data signal does not indicate that the patient is havingand/or has had a seizure accompanied by tachycardia, the methodcomprises applying a first electrical signal to a left vagus nerve. Ifthe body signal does indicate that the patient has experienced a seizureaccompanied by tachycardia, the method comprises applying a secondelectrical signal to a right vagus nerve.

Without being bound by theory, it is believed that stimulation of theright vagus nerve, which enervates the right sinoatrial nerve thatfunctions as the heart's natural pacemaker, will have a more prominenteffect in slowing the heart rate than stimulation of the left vagusnerve. The present disclosure takes advantage of this electricalasymmetry of the left and right vagus nerves to minimize the effect ofVNS on heart rate except where there is a need for acute intervention toslow the heart rate, i.e., when the patient has experienced andepileptic seizure, and the seizure is accompanied by an increase inheart rate. This may result in, for example, stimulation of the leftvagus nerve either when there is no seizure (such as when an open-loopstimulation program off-time has elapsed and the program initiatesstimulation in accordance with a programmed signal on-time), or whenthere is a detected seizure event that is not accompanied by an increasein heart rate (such as absence seizures); and stimulation of the rightvagus nerve when there is a detected seizure event accompanied by aheart rate increase. In one embodiment, a programmed, open-loopelectrical signal is applied to the left vagus nerve except when analgorithm analyzing the acquired body signal detects a seizureaccompanied by a heart rate increase. In response to such a detection, aclosed-loop electrical signal is applied to the right vagus nerve toslow the patient's (increased) heart rate. In some embodiments, theresponse to detecting a seizure accompanied by a heart rate increase mayalso include interrupting the application of the programmed-open-loopelectrical signal to the left vagus nerve. The interrupted open-loopstimulation of the left vagus nerve may be resumed either when theseizure ends or the heart rate returns to a desired, lower heart rate.

In an additional embodiment of the disclosure, electrode pairs may beapplied to each of the left and right vagus nerves of the patient, andused depending upon whether or not seizures accompanied by cardiacchanges such as tachycardia are detected.

FIG. 8 is a flowchart depiction of a method of treating patients havingseizures accompanied by a relative or absolute decrease in heart rate(i.e., a bradycardia episode). Epileptic seizures originating fromcertain brain regions may trigger decreases in heart rate of a magnitudesufficient to cause loss of consciousness and of postural tone (i.e.,syncope). In some subjects the cerebral ischemia associated with thebradycardia may in turn lead to convulsions (i.e., convulsive syncope).If bradycardia-inducing seizures are not controllable by medications,the current treatment is implantation of a demand cardiac pacemaker. Inone embodiment of the present disclosure, ictal bradycardia may betreated by preventing vagal nerve impulses from reaching the heart,either by preventing impulses traveling through all fiber typescontained in the trunk of the nerve or in one of its branches, or byonly blocking impulses within a certain fiber type. In anotherembodiment, the degree of the nerve impulse blocking within a vagusnerve may be determined based upon the magnitude of bradycardia (e.g.,the larger the bradycardia change from the pre-existing baseline heartrate, the larger the magnitude of the block) so as to preventtachycardia from occurring.

In one embodiment, a body signal is acquired (810). The body signal maycomprise one or more body signals that may be altered, changed orinfluenced by an epileptic seizure. Changes in the body signal may beused to detect the onset or impending onset of seizures. As noted withreference to FIG. 7, the body signal may comprise one or more measurederived from a cardiac signal (e.g., heart rate, heart rate variability,change in EKG morphology), a kinetic signal (e.g., an accelerometer,force of muscle contraction, posture or body position signal), bloodpressure, blood oxygen concentration, skin resistivity/conductivity,pupil dilation, eye movement, or other body signals. The body signal maybe a real-time signal, a near-real-time signal, or a non-real-timesignal, although in preferred embodiments, the signal is a real-timesignal or a near-real-time signal. The signal may be acquired from asensor element (e.g., coupled to a processor) or from a storage device.

Referring again to FIG. 8, the method further comprises determiningwhether or not the patient is having and/or has had a seizure that isaccompanied by a decrease in heart rate (820). In one embodiment, themethod comprises using a seizure detection algorithm using one or moreof a cardiac, kinetic, neurologic, endocrine, metabolic or tissue stressmarker to detect seizures, and to determine if the seizure is associatedwith a decrease in heart rate. In a particular embodiment, analgorithm—which may comprise software and/or firmware running in aprocessor in a medical device—analyzes one or more of a cardiac signal,a kinetic signal, blood pressure, blood oxygen concentration, skinresistivity or conductivity, pupil dilation, and eye movement toidentify changes in the one or more signals that indicate the occurrenceof an epileptic seizure. Such changes may be identified by determiningone or more indices from the foregoing signals, such as a cardiac index(e.g., a heart rate), a kinetic index (e.g., a kinetic level or motiontype, a magnitude of an acceleration or force, or other indices that maybe calculated from an accelerometer signal). The method may includeproviding an output signal or setting a data flag when the detectionalgorithm determines from the body signal(s) that the patient is havingand/or has had a seizure. In a preferred embodiment, the seizuredetection occurs in real time and the output signal or data flag is setimmediately upon detection of the seizure.

Once it is determined that the patient is having and/or has had aseizure, the method also comprises determining if the seizure isaccompanied by a decrease in heart rate. In one embodiment, the acquiredbody data signal (810) comprises a heartbeat signal that may be analyzedto determine heart rate. In some embodiments, the acquired heart beatsignal may be used by the seizure detection algorithm to determinewhether a seizure has occurred, while in other embodiments seizures aredetermined without regard to the patient's heart rate. Regardless of howthe seizure is determined, the method of FIG. 8 comprises determiningwhether a detected seizure event is accompanied by a decrease in heartrate (820). The decrease in heart rate may be determined in a variety ofways, such as by a decrease in an instantaneous heart rate below areference heart rate value (which may be a predetermined interictalvalue such as 72 beats per minute (bpm), or a real-time measure ofcentral tendency for a time window or number-of-beats window (e.g., a 5minute median or moving average heart rate, or a media heart rate for awindow selected from 3-300 beats such as a 5, 10, or 300 beat window)).Additional details about identifying decreases in heart rate in thecontext of epileptic seizures are provided in U.S. patent applicationSer. Nos. 12/770,562, 12/771,727, 12/771,783, 12/884,051, 12/886,419,13/091,033, each of which is hereby incorporated by reference in itsentirety herein.

In one embodiment, if the acquired body data signal does not indicatethat the patient is having and/or has had a seizure accompanied by a HRdecrease, the method comprises applying a first electrical signal to avagus nerve (840), wherein the first electrical signal is sufficient togenerate exogenous action potentials in fibers of the vagus nerve. Thesecond electrical signal is a therapeutic electrical signal to treat theseizure. It may be applied to either the left or right vagus nerves, orboth. The first electrical signal may be a signal defined by, amongother parameters, an on-time during which electrical pulses are appliedto the nerve, and an off-time during which no pulses are applied to thenerve. In some embodiments, the on-time may be determined by theduration and intensity of the change in heart rate, while in otherembodiments it may be pre-programmed Cathode(s) and anode(s) may beplaced on the nerve trunks or branches to maximize flow of exogenouslygenerated nerve impulses in a caudal direction (for control of heartrate changes) and a cephalic direction for seizure treatment.

If the body signal indicates that the patient is having and/or has had aseizure accompanied by a decrease in heart rate, the method comprisesapplying an action to decrease vagal/parasympathetic tone. In oneembodiment, the method comprises blocking the passage of impulsesthrough at least one of a vagus nerve trunk or branch. This may beaccomplished by applying one or more of a second electrical signal(e.g., a high frequency electrical signal), a thermal signal (e.g.,cooling), a chemical signal (e.g., applying a local anesthetic), and/ora mechanical signal (e.g., applying pressure or a vibration) to a vagusnerve of the patient (830). In another embodiment, the method comprisesdelivering at least one of an anti-cholinergic drug or asympatho-mimetic drug.

As used herein, blocking vagus nerve activity means blocking intrinsicor native vagal activity (i.e., blocking action potentials notartificially or exogenously induced by an electrical signal generated bya device). The blocking signal may block the conduction of actionpotentials in all or at least some portion or fraction of the axons of avagus nerve. In general, such blocking signals are incapable of inducingexogenous action potentials in the axons of the vagus nerve. In oneembodiment, the blocking signal may comprise a high frequency, pulsedelectrical signal, the pulse frequency being sufficient to inhibitpropagation of at least some action potentials in vagus nerve fibers.The electrical signal may comprise a signal in excess of 300 Hz, orother frequency, so long as the frequency and other stimulation signalparameters (such as pulse width and pulse current or voltage) provide asignal capable of inhibiting some or all of the action potentialspropagating along fibers of the vagus nerve. In alternative embodiments,the electrical signal may comprise generating unidirectional actionpotentials for collision blocking of endogenous action potentials.

High frequency vagus nerve stimulation (or other blocking signals suchas collision blocking) may inhibit pathological vagus nerve activityassociated with the seizure that may be acting to slow the patient'sheart rate. By providing such stimulation only when the patientexperiences a seizure accompanied by a reduced heart rate (e.g.,bradycardia), a therapy may be provided that acts to maintain thepatient's heart rate when the patient experiences a seizure involvingexcessive vagal activity—and consequent undesired slowing of—the heart.In one embodiment, the blocking electrical signal (830) is provided to aright vagus nerve. Without being bound by theory, because the rightvagus nerve innervates the right sinoatrial node that functions as theheart's natural pacemaker, it is believed that right-side VNS will havea more significant effect upon the heart rate than stimulation of theleft vagus nerve. In alternative embodiments, the blocking signal may beapplied to the left vagus nerve, to both the right and left vagusnerves, or to one or both of the left and right cardiac branches of thevagus nerves.

In one embodiment, the method comprises applying a first electricalsignal that may be a conventional vagus nerve stimulation signal definedby a plurality of parameters (e.g., a pulse width, a current magnitude,a pulse frequency, an on-time and an off-time). A seizure detectionalgorithm (e.g., using one or more of a cardiac, kinetic, metabolic,EEG, or other body signal) may be used to detect seizures, and thepatient's heart rate may be determined proximate the seizure detectionto determine if the seizure is accompanied by a decrease in thepatient's heart rate. If the seizure is accompanied by a slowing of thepatient's heart rate, the first electrical signal may be suspended, anda second electrical signal may be applied to slow the patient's heartrate. The method may further include sensing the patient's heart rateduring or after application of the second electrical signal. In oneembodiment, the second electrical signal may be modified (e.g., bychanging current magnitude, pulse width, or pulse frequency), orsuspended (and possibly resumed) to maintain the patient's heart ratebetween an upper heart rate threshold and a lower heart rate threshold.In some embodiments, the upper and lower heart rate thresholds may bedynamically set (e.g., as no more than 5 bpm above or below the baselineHR prior to the seizure detection).

FIG. 9 is a flow diagram of a method of treating a patient with epilepsyby providing closed-loop vagus nerve intervention (e.g., stimulation orblockage of impulse conduction) to maintain the patient's heart ratewithin a range that is both safe and also commensurate with the activitytype or level and state of the patient (e.g., as determined from akinetic signal from a sensing element such as a triaxial accelerometeror by measuring oxygen consumption). In one embodiment, the methodcomprises providing vagus nerve stimulation in response to determiningthat a heart rate is incommensurate with the kinetic signal of thepatient, to restore cardiac function to a rate that is commensurate withthe patient's kinetic signal. In one embodiment, the stimulation maycomprise stimulating a right vagus nerve to slow the patient's heartrate to a level that is safe and/or commensurate with activity level. Inanother embodiment, the stimulation may comprise providing a blockingsignal to increase a slow heart rate to a rate that is safe and/orcommensurate with the activity level. Pharmacologic compounds (e.g.,drugs) with sympathetic or parasympathetic effects (e.g., enhancing orblocking sympathetic or parasympathetic activity) may be used to restoreheart rate to a rate commensurate with kinetic activity of the patientin still other embodiments. In one embodiment, the method involvesdetermining a heart rate and one or more kinetic or metabolic (e.g.,oxygen consumption) indices for the patient (910). Heart rate may bedetermined from an acquired cardiac signal (e.g., from a sensor orstored data). Kinetic and/or metabolic indices may likewise bedetermined from a kinetic sensor (e.g., an accelerometer, a positionalsensor, a GPS device coupled to a clock, or a postural sensor), ametabolic sensor, or from stored data. Sensor data may be subjected toone or more operations such as amplifying, filtering, A/D conversion,and/or other pre-processing and processing operations to enabledetermination of heart rate (and in some embodiments other cardiacindices such as heart rate variability) and kinetic indices.

The activity level of the patient may be determined from multiplekinetic indications such as an activity level, a type of activity, aposture, a body position, a trunk or limb acceleration or force, or aduration of one of the foregoing, and may be adapted or modified as afunction of age, gender, body mass index, fitness level or time of dayor other indices of the patient's condition or environment. For example,the kinetic signal may be processed to provide indices that indicatemoderate ambulatory motion for an upright patient, vigorous physicalexercise (in which the patient may be upright as in running or in aprone position as in some calisthenics exercises), a fall (e.g.,associated with a seizure), reclining, resting or sleeping, among otheractivity levels and kinetic states.

The one or more kinetic indices may then be used to determine (e.g., byretrieving stored data from a lookup table or by calculation using analgorithm) one or more heart rate ranges or values that would becommensurate with the kinetic activity and/or kinetic state, duration,time of day, etc. associated with the indices. In some embodiments,heart rate ranges may be established for particular levels or types ofactivity (e.g., running, walking), that may be adaptively adjusteddepending upon various factors such as the duration of the activity, thepatient's fitness level, the time of day, a level of fatigue, anenvironmental temperature, etc. A commensurate heart rate is one that iswithin expected ranges or values for the person's effort, and forfactors inherent to the patient and the environment.

Returning to FIG. 9, the determined heart rate may be compared to therange(s)/value(s) identified as commensurate with the kinetic indices(920) at a given time point. If the actual heart rate of the patient iswithin the expected/commensurate range or value associated with thekinetic or metabolic indices at the time point, or is within a specifiedproximity of a particular range or value, no action may be taken, andthe method may involve continuing to analyze the patient's cardiac andkinetic signals or metabolic signals. On the other hand, if the heartrate is outside the expected value or range of values for the kinetic ormetabolic indices for that time point, then the heart rate is notcommensurate with the kinetic signal of the patient, and a therapy maybe provided to the patient by applying one of an electrical, thermal,mechanical or chemical signal to a vagus nerve of the patient (930) oradministering to the patient (e.g., intravenously, through mucosae) adrug with cholinergic or anti-cholinergic or adrenergic actions,depending on the case or situation. In one embodiment, the method maycomprise applying the signal to a main trunk of a vagus nerve of thepatient, and in another embodiment, the signal may be applied to acardiac branch of a vagus nerve.

In one embodiment, the heart rate of the patient may be higher than avalue commensurate with the activity level or kinetic indices of thepatient. In this case, the patient is having relative tachycardia. Wherethis is the case, as previously noted, vagus nerve stimulation may beapplied to one or more of a right cardiac branch, left cardiac branch,or right main trunk of the patient's vagus nerve to reduce the patient'sheart rate to a rate that is commensurate with the activity level.Embodiments of the disclosure may be used to treat epileptic seizuresassociated with tachycardia, and other medical conditions associatedwith tachycardia given the patient's activity level. Therapies (e.g.,electrical, chemical, mechanical, thermal) delivered to a patient viathe vagus nerves may be employed for tachyarrythmias, angina pectoris orpain in regions innervated by a vagus nerve.

In another embodiment, the patient's heart rate may be lower than avalue commensurate with the patient's activity level or kinetic indices,that is, the patient is having relative or absolute bradycardia. Highfrequency (>>300 Hz) electrical pulses may be applied to the left orright vagus nerves (e.g., a main trunk of the right and/or left vagusnerves or to their cardiac branches) to block propagation oftransmission of nerve impulses through their fibers. High-frequency VNSmay be applied to block impulses traveling to the heart to abateneurogenic, cardiogenic or iatrogenic bradycardia, or to minimize thecumulative effects on the heart's conduction system and myocardium ofepileptic seizures, especially in status epilepticus. Selective blockageof impulses traveling through a vagus nerve to the heart may beaccomplished with electrical stimulation to treat adverse cardiaceffects associated with disorders such as epilepsy, depression, diabetesor obesity. By blocking vagus nerve conduction to the heart, when thepatient's heart rate is incommensurate with the activity level orkinetic indices, a therapy may be provided to revert the change in heartrate (whether the change involves bradycardia or tachycardia). In oneembodiment, an electrical signal generator may be used to apply a firsttherapy signal to a vagus nerve of the patient, and an electrical signalgenerator (which may be the same or a different electrical signalgenerator) may apply a vagus nerve conduction blocking electrical signalto a vagus nerve (e.g., a cardiac branch of the vagus nerve) to blockcardiac effects that would result from the first electrical signal,absent the vagus nerve conduction blocking electrical signal.

Referring again to FIG. 9, the method may comprise determining thepatient's heart rate in response the therapy to determine whether theheart rate has been restored to a rate that is with commensurate withthe patient's activity level/kinetic index (940). If not, then thetherapy (e.g., VNS to reduce or increase heart rate to an appropriatevalue) may be continued, with or without parameter modification, orre-initiated after a delay period or confirmation period.

If the heart rate has returned to a range/value commensurate with theactivity level of the patient, the method may, in some embodiments,further involve determining whether or not an adverse event has occurred(950). Adverse events may include, without limitation, side effects suchas voice alteration, pain, difficulty breathing or other respiratoryeffects, adverse cardiac effects such as bradycardia (following adetermination of relative tachycardia in step 920), tachycardia(following a determination of bradycardia in step 920), and alterationin blood pressure or gastro-intestinal activity.

If an adverse event has occurred, the method may involve changing one ormore stimulation parameters to eliminate, reduce or ameliorate theadverse event (955). If no adverse event has occurred, the method maycomprise continuing to apply a signal the vagus nerve until apredetermined signal application duration has been reached (960), atwhich time the signal application may be stopped (970). The method mayfurther comprise determining, after the therapy has been stopped, if thepatient's heart rate remains incommensurate with the patient's activitylevel or type (980), in which case the signal application may be resumedor other appropriate action may be taken (e.g., local or remote alarmsor alerts, notification of caregivers/healthcare providers, etc.). Ifthe heart rate has returned to a value that is commensurate orappropriate for the patient's activity level, the signal application maybe discontinued (990).

FIG. 10 is a flow diagram of a method of treating a patient to withepilepsy by providing closed-loop vagus nerve stimulation to treatrelative tachycardia or relative bradycardia by restoring the patient'sheart rate to a rate that is commensurate with the activity type orlevel of the patient (e.g., as determined from a kinetic signal from asensing element such as a triaxial accelerometer or by measuring oxygenconsumption). In one embodiment, the method comprises identifyinginstances of relative tachycardia or relative bradycardia and respondingwith negative or positive chronotropic actions to restore the heart rateto a level commensurate with the patient's activity type or level.

In one embodiment, the method involves determining a heart rate and anactivity type or level for the patient (1010). The patient's heart ratemay be determined from an acquired cardiac signal or from stored data.The activity level or type of the patient may be determined from one ormore sensor or from stored data. Sensors may include, for example,accelerometers, positional sensors, GPS devices coupled to a clock,postural sensors, and metabolic sensors. Sensor data may be subject toconventional signal processing, and may in addition be adapted ormodified as a function of age, gender, body mass index, fitness level ortime of day or other indices of the patient's condition or environment.

The patient's activity type or level may then be used to determine oneor more heart rate ranges or values that are commensurate with theactivity type or level (1020). In some embodiments, heart rate rangesmay be established for particular levels or types of activity (e.g.,running, walking), that may be adaptively adjusted depending uponvarious factors such as the duration of the activity, the patient'sfitness level, the time of day, a level of fatigue, an environmentaltemperature, etc. A commensurate heart rate is one that is withinexpected ranges or values for the person's effort, and for factorsinherent to the patient and the environment.

If the heart rate is commensurate with the activity level, in oneembodiment no action may be taken, and the method may involve continuingto analyze the patient's cardiac and activity. On the other hand, if theheart rate is outside the identified value or range of valuesappropriate for the patient's activity type or level then the heart rateis not commensurate with the kinetic signal of the patient. Where thisis the case, the method may further comprise determining whether thepatient is experiencing relative tachycardia or is experiencing relativebradycardia (1030, 1040).

Where the heart rate of the patient is higher than a value commensuratewith the activity level or type, the patient is experiencing relativetachycardia (1030), and the method may comprise initiating a negativechronotropic action (1035) to slow the heart rate to a rate that iscommensurate with the activity level or type. In one embodiment, thismay involve applying stimulation to one or more of a left or right mainvagal trunk or cardiac branch of the patient. In other embodiments, themethod may comprise providing a drug to enhance the parasympathetic toneof the patient. In still other embodiments, the method may comprisereducing the patient's sympathetic tone, such as by applyinghigh-frequency stimulation to a sympathetic nerve trunk or ganglion oradministering an anti-cholinergic drug. Negative chronotropic actionsmay be used to treat epileptic seizures associated with tachycardia, andother medical conditions associated with relative tachycardia given thepatient's activity level.

Where the heart rate of the patient is lower than a value commensuratewith the activity level or type, the patient is experiencing relativebradycardia (1040), and the method may comprise initiating a positivechronotropic action (1045) to increase the heart rate to a rate that iscommensurate with the activity level or type. In one embodiment, thismay involve applying high-frequency (>>300 Hz) electrical stimulation toone or more of a left or right main vagal trunk or cardiac branch of thepatient to reduce the transmission of intrinsic vagus nerve actionpotentials in at least some vagal fibers. In other embodiments, themethod may comprise providing a drug to reduce the parasympathetic toneof the patient. In still other embodiments, the method may compriseincreasing the patient's sympathetic tone, such as by applyingelectrical signals to a sympathetic nerve trunk or ganglion or byadministering a sympatho-mimetic drug. Positive chronotropic actions maybe used to treat epileptic seizures associated with bradycardia, andother medical conditions associated with relative bradycardia given thepatient's activity level.

The method may further comprise, after initiating the negative orpositive chronotropic action, determining whether the patient's heartrate has been restored to a rate that is with commensurate with thepatient's activity level/kinetic index (1050). If not, then the therapy(e.g., VNS to reduce or increase heart rate to an appropriate value) maybe continued, with or without parameter modification, or re-initiatedafter a delay period or confirmation period.

If the heart rate has returned to a range/value commensurate with theactivity level of the patient, the method may, in some embodiments,further involve determining whether or not an adverse event has occurred(1060). Adverse events may include, without limitation, side effectssuch as voice alteration, pain, difficulty breathing or otherrespiratory effects, adverse cardiac effects such as bradycardia(following a determination of relative tachycardia in step 1030), ortachycardia (following a determination of bradycardia in step 1040), andalteration in blood pressure or gastric activity.

If an adverse event has occurred, the method may involve changing one ormore stimulation parameters to eliminate, reduce or ameliorate theadverse event (1070). If no adverse event has occurred, the method maycomprise continuing to stimulate the vagus nerve (or a chemical, thermalor mechanical therapy) until a predetermined stimulation duration hasbeen reached (1075), at which time the stimulation may be stopped(1080). The method may further comprise determining, after the therapyhas been stopped, if the patient's heart rate remains incommensuratewith the patient's activity level or type (1090), in which case thestimulation may be resumed or other appropriate action may be taken(e.g., local or remote alarms or alerts, notification ofcaregivers/healthcare providers, use of other forms of therapy, etc.).If the heart rate has returned to a value that is commensurate orappropriate for the patient's activity level, the stimulation may bediscontinued (1095).

Additional embodiments consistent with the foregoing description andfigures may be made. Non-limiting examples of some such embodiments areprovided in the numbered paragraphs below.

100. A method of controlling a heart rate of an epilepsy patientcomprising:

sensing at least one of a kinetic signal and a metabolic signal of thepatient;

analyzing the at least one of a kinetic and a metabolic signal todetermine at least one of a kinetic index and a metabolic index;

receiving a cardiac signal of the patient;

analyzing the cardiac signal to determine the patient's heart rate;

determining if the patient's heart rate is commensurate with the atleast one of a kinetic index and a metabolic index; and

applying an electrical signal to a vagus nerve of the patient based on adetermination that the patient's heart rate is not commensurate with theat least one of a kinetic signal and a metabolic signal of the patient.

101. The method of numbered paragraph 100, wherein determining at leastone of a kinetic index and a metabolic index comprises determining atleast one of an activity level or an activity type of the patient basedon the at least one of a kinetic index and a metabolic index, andwherein determining if the patient's heart rate is commensurate with theat least one of a kinetic index and a metabolic index of the patientcomprises determining if the heart rate is commensurate with the atleast one of an activity level or an activity type.

102. The method of numbered paragraph 101, wherein determining if thepatient's heart rate is commensurate with the at least one of a kineticindex and a metabolic index comprises determining if the patient's heartrate is above or below a rate that is commensurate with the one or moreof a kinetic index and a metabolic index.

103. A method of treating a patient having epilepsy comprising

sensing at least one body signal of the patient;

determining whether or not the patient is having or has had an epilepticseizure based on the at least one body signal;

sensing a cardiac signal of the patient;

determining whether or not the seizure is associated with a change inthe patient's cardiac signal;

applying a first therapy to a vagus nerve of the patient based on adetermination that the patient is having or has had an epileptic seizurethat is not associated with a change in the patient's cardiac signal,wherein the first therapy is selected from an electrical, chemical,mechanical, or thermal signal; and

applying a second therapy to a vagus nerve of the patient based on adetermination that the patient is having or has had an epileptic seizureassociated with a change in the patient's cardiac signal, wherein thesecond therapy is selected from an electrical, chemical, mechanical(e.g., pressure) or thermal signal.

104. The method of numbered paragraph 103, further comprising applying athird therapy to a vagus nerve of the patient based a determination thatthe patient is not having or has not had an epileptic seizure, whereinthe third therapy is selected from an electrical, chemical, mechanicalor thermal signal.

105. A method of treating a patient having epilepsy comprising:

coupling a first set of electrodes to a main trunk of the left vagusnerve of the patient;coupling a second set of electrodes to a main trunk of the right vagusnerve of the patient;providing an electrical signal generator coupled to the first electrodeset and the second electrode set;receiving at least one body data stream;

analyzing the at least one body data stream using a seizure detectionalgorithm to determine whether or not the patient is having and/or hashad an epileptic seizure;

applying a first electrical signal from the electrical signal generatorto the main trunk of the left vagus nerve, based on a determination thatthe patient is having and/or has had an epileptic seizure without aheart rate change; and

applying a second electrical signal from the electrical signal generatorto the main trunk of the right vagus nerve, based on a determinationthat the patient is having or has had an epileptic seizure with a heartrate change.

106. A method of treating a patient having epilepsy comprising:

receiving at least one body data stream;

analyzing the at least one body data stream using a seizure detectionalgorithm to detect whether or not the patient has had an epilepticseizure;

receiving a cardiac signal of the patient;

analyzing the cardiac signal to determine a first cardiac feature;

applying a first electrical signal to a vagus nerve of the patient,based on a determination that the patient has not had an epilepticseizure characterized by a change in the first cardiac feature, whereinthe first electrical signal is not a vagus nerve conduction blockingelectrical signal; and

applying a second electrical signal to a vagus nerve of the patient,based on a determination that the patient has had an epileptic seizurecharacterized by a change in the cardiac feature, wherein the secondelectrical signal is a pulsed electrical signal that blocks actionpotential conduction in the vagus nerve.

107. A method of treating a patient having epilepsy comprising:

receiving at least one body data stream;

analyzing the at least one body data stream using a seizure detectionalgorithm to detect whether or not the patient has had an epilepticseizure;

receiving a cardiac signal of the patient;

analyzing the cardiac signal to determine a first cardiac feature;

applying a first electrical signal to a vagus nerve of the patient,based on a determination that the patient has not had an epilepticseizure characterized by a change in the first cardiac feature, whereinthe first electrical signal is a pulsed electrical signal that blocksaction potential conduction in the vagus nerve; and

applying a second electrical signal to a vagus nerve of the patient,based on a determination that the patient has had an epileptic seizurecharacterized by a change in the cardiac feature, wherein the secondelectrical signal is not a vagus nerve conduction blocking electricalsignal.

In FIG. 11, a graph of heart rate versus time is shown, according to oneembodiment. A first graph 1100 includes a y-axis 1102 which representsheart rate where the heart rate goes from a zero value to an Nth value(e.g., 200 heart beats, etc.). Further, the first graph 1100 includes anx-axis 1104 which represents time from 1 minute to Nth minutes (and/or0.001 seconds to Nth seconds). In this example, a first heart rateversus time line 1106 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 118 heartbeats per minute with a first rise 1108A and a first run 1108B during afirst event 1108C. In addition, the patient's heart rate goes from 70heart beats per minute to 122 heart beats per minute during a secondevent 1108D which has a first percentage change 1110 associated with thesecond event 1108D. Further, the patient's heart rate goes from 70 beatsper minute to 113 beats per minute during an nth event 1108E whichsurpasses a first threshold amount 1112, and/or a second thresholdamount 1114, and/or an Nth threshold amount 1116. In one example, onlythe Nth threshold amount 1116 needs to be reached to trigger a therapyand/or an alert. In another example, only the second threshold amount1114 needs to be reached to trigger a therapy and/or an alert. Inanother example, only the first threshold 1112 needs to be reached totrigger a therapy and/or an alert. In another example, both the Nththreshold 1116 and the second threshold 1114 need to reached to triggera therapy and/or an alert. In another example, all of the Nth threshold1116, the second threshold 1114 and the first threshold 1112 need toreached to trigger a therapy and/or an alert. In one example, only theNth threshold amount 1116 needs to be reached during a specific timeperiod to trigger a therapy and/or an alert. In another example, onlythe second threshold amount 1114 needs to be reached during a specifictime period to trigger a therapy and/or an alert. In another example,only the first threshold 1112 needs to be reached during a specific timeperiod to trigger a therapy and/or an alert. In another example, boththe Nth threshold 1116 and the second threshold 1114 need to reachedduring a specific time period to trigger a therapy and/or an alert. Inanother example, all of the Nth threshold 1116, the second threshold1114 and the first threshold 1112 need to reached during a specific timeperiod to trigger a therapy and/or an alert. In these examples, one ormore triggering events may occur based on a determination of the riseand run of a change in heart rate, a percentage change in heart rate, athreshold amount being reached or exceeded (or within any percentage ofthe threshold), and/or any combination thereof. A triggering event mayinitiate one or more actions to increase and/or decrease the patient'sheart rate. For example, if the patient's heart rate is increasing whichdetermines the triggering event, then the system, device, and/or methodmay initiate one or more actions to decrease the heart rate of thepatient to help reduce, dampen, eliminate, and/or buffer the increase inthe patient's heart rate. Further, the system, device, and/or method mayoscillate between decreasing the patient's heart rate and increasing thepatient's heart rate depending on any changes to the patient's heartrate. For example, the system, device, and/or method may initiate one ormore actions to decrease a patient's heart rate based on the patient'sheart rate going from 80 heart beats per minute to 130 heart beats perminute which results in the patient's heart rate falling from 130 heartbeats per minute to 65 heart beats per minute in a first time period.Based on the change in the heart rate from 130 heart beats per minute to65 heart beats per minute in the first time period, the system, device,and/or method may initiate one or more actions to increase the patient'sheart rate and/or stabilize the patient's heart rate. In anotherexample, the system, method, and/or device may stop and/or modify anyinitiated action based on one or more feedback signals. In addition, oneor more warnings may be transmitted to the patient, a caregiver, adoctor, a medical professional, and/or logged.

In FIG. 12, another graph of heart rate versus time is shown, accordingto one embodiment. A second graph 1200 illustrating a second heart rateversus time line 1202 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 120 heartbeats per minute which creates a first system alert event 1204 (e.g.,A1). Further, the system, device, and/or method initiates a firsttherapy 1206 (e.g., X1) based on the first system alert event 1204. Inaddition, a second system alert event 1208 (e.g., A2) occurs and asecond therapy 1210 (e.g., X2) is initiated based on the second systemalert event 1208. In addition, a third system alert event 1212 (e.g.,A3) occurs and a third therapy (e.g., X3) 1214 is initiated based on thethird system alert event 1212 (e.g., A3). In addition, a fourth systemalert event 1216 (e.g., A4) occurs and a fourth therapy 1218 (e.g., X4)is initiated based on the fourth system alert event 1216 (e.g., A3).Further, a fifth therapy 1220 (e.g., X5) is initiated based on theeffects of the fourth therapy 1218 (e.g., X4). In addition, a fifthsystem alert event 1222 (e.g., A5) occurs and a sixth therapy (e.g., X6)1224 is initiated based on the fifth system alert event 1222 (e.g., A5).In addition, a sixth system alert event 1226 (e.g., A6) occurs and aseventh therapy (e.g., X7) 1228 is initiated based on the sixth systemalert event 1226 (e.g., A6). In addition, a seventh system alert event1230 (e.g., A7) occurs and an eighth therapy (e.g., X8) 1232 isinitiated based on the seventh system alert event 1230 (e.g., A7). Inaddition, a first stop stimulation event 1234 (e.g., B1) occurs whichturns off all therapies and/or system alerts may occur when the heartrate returns to the approximate starting heart rate and/or a targetvalue. In these examples shown with FIG. 12, a rise over run heart ratecalculation was completed to determine the one or more system alerts.However, it should be noted that any calculation (e.g., % increase, %decrease, etc. can be utilized). Further, all systems alerts and/ortherapies may occur as independent events and/or examples. For example,the seventh system alert may be the first system alert in a specificexample. In other words, no other events and/or therapies occurredbefore the seventh system alert. Therefore, the seventh system alertbecomes the first system alert. In addition, one or more warnings may betransmitted to the patient, a caregiver, a doctor, a medicalprofessional, and/or logged. In addition, there may be up to an Nthalerts, an Nth stop stimulation (and/or therapy) event, and an Nththerapy in any of the examples disclosed in this document.

In FIG. 13, another graph of heart rate versus time is shown, accordingto one embodiment. A third graph 1300 illustrating a third heart rateversus time line 1302 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 116 heartbeats per minute which creates a first system alert event 1304 (e.g.,A1). Further, the system, device, and/or method initiates a firsttherapy 1306 (e.g., X1) based on the first system alert event 1304. Inaddition, a first stop stimulation event 1308 (e.g., B1) occurs whichturns off all therapies and/or system alerts occurs when the heart ratereturns to the approximate starting heart rate and/or a target value.Further, the patient's heart rate goes from 80 heart beats per minute to123 heart beats per minute which creates a second system alert event1310 (e.g., A2). Further, the system, device, and/or method initiates asecond therapy 1312 (e.g., X2) based on the second system alert event1310. In addition, a second stop stimulation event 1314 (e.g., B2)occurs which turns off all therapies and/or system alerts occurs whenthe heart rate returns to the approximate starting heart rate and/or atarget value. In these examples shown with FIG. 13, a percentage changein heart rate calculation was completed to determine the one or moresystem alerts. However, it should be noted that any calculation (e.g.,rise over run, etc. can be utilized). Further, all systems alerts and/ortherapies may occur as independent events and/or examples. For example,the second system alert may be the first system alert in a specificexample In other words, no other events and/or therapies occurred beforethe second system alert. Therefore, the second system alert becomes thefirst system alert. In addition, one or more warnings may be transmittedto the patient, a caregiver, a doctor, a medical professional, and/orlogged.

In FIG. 14, another graph of heart rate versus time is shown, accordingto one embodiment. A fourth graph 1400 illustrating a fourth heart rateversus time line 1402 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 120 heartbeats per minute which creates a first system alert event 1404 (e.g.,A1) because the 120 heart beats per minutes meets or exceeds a firstthreshold value 1416 (e.g., 115 heart beats per minute). In thisexample, a second system alert event 1406 (e.g., A2) is created becausethe heart beats of the patient meets or exceeds the first thresholdvalue 1416 (e.g., 115 heart beats per minute). Further, the system,device, and/or method initiates a first therapy 1408 (e.g., X1) based onthe first system alert event 1404 and the second system alert event 1406occurring. The first system alert event 1404 and the second system alertevent 1406 may be time dependent. For example, the first system alertevent 1404 and the second system alert event 1406 may have to occurwithin a first time period for the initiation of the first therapy 1408.In another example, the first system alert event 1404 and the secondsystem alert event 1406 may not be time dependent. Further, a thirdsystem alert event 1410 (e.g., A3) is created because the heart beats ofthe patient meets or exceeds (and/or within a specific rate of thethreshold—in this example within 5 percent—heart rate is 110) the firstthreshold value 1416 (e.g., 115 heart beats per minute). Further, thesystem, device, and/or method initiates a second therapy 1412 (e.g., X2)based on the first system alert event 1404, the second system alertevent 1406, and/or the third system event occurring. It should be notedthat the second therapy 1412 has a time delay factor utilized with thesecond therapy 1412. In another example, no time delay is utilized. Inaddition, one or more time delays can be used with any therapy, anywarning, and/or any alert in this document. The first system alert event1404, the second system alert event 1406, and the third system alertevent 1410 may be time dependent. For example, the first system alertevent 1404, the second system alert event 1406, and the third systemalert event 1410 may have to occur within a first time period for theinitiation of the second therapy 1412. In another example, the firstsystem alert event 1404, the second system alert event 1406, and thethird system alert event 1410 may not be time dependent. Further, afirst stop stimulation event 1414 (e.g., B1) occurs which turns off alltherapies and/or system alerts occurs when the heart rate returns to theapproximate starting heart rate and/or a target value. Further, allsystems alerts and/or therapies may occur as independent events and/orexamples. For example, the third system alert may be the first systemalert in a specific example. In other words, no other events and/ortherapies occurred before the third system alert. Therefore, the thirdsystem alert becomes the first system alert. In addition, one or morewarnings may be transmitted to the patient, a caregiver, a doctor, amedical professional, and/or logged.

In FIG. 15, another graph of heart rate versus time is shown, accordingto one embodiment. A fifth graph 1500 illustrating a fifth heart rateversus time line 1502 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 40 heartbeats per minute which creates a first system alert event 1504 (e.g.,A1) because the 40 heart beats per minutes meets or exceeds a firstthreshold value 1520 (e.g., 50 heart beats per minute). It should benoted that no alert was generated when the heart rate fell to 52 heartbeats per minute because 52 heart beats per minute is above thethreshold value of 50 heart beats per minute. Further, the system,device, and/or method initiates a first therapy 1506 (e.g., X1) based onthe first system alert event 1504 occurring. Further, the patient'sheart rate goes from 80 heart beats per minute to 50 heart beats perminute which creates a second system alert event 1508 (e.g., A2) becausethe 50 heart beats per minutes meets or exceeds the first thresholdvalue 1520 (e.g., 50 heart beats per minute). Further, the system,device, and/or method initiates a second therapy 1510 (e.g., X2) basedon the second system alert event 1508 occurring. Further, a first stopstimulation event 1512 (e.g., B1) occurs which turns off all therapiesand/or system alerts occurs when the heart rate returns to theapproximate starting heart rate and/or a target value. In addition, thepatient's heart rate goes from 80 heart beats per minute to 45 heartbeats per minute which creates an nth system alert event 1514 (e.g., A3)because the 45 heart beats per minutes meets or exceeds the firstthreshold value 1520 (e.g., 50 heart beats per minute). Further, thesystem, device, and/or method initiates an Nth therapy 1516 (e.g., X3)based on the nth system alert event 1514 occurring. Further, an nth stopstimulation event 1518 (e.g., B2) occurs which turns off all therapiesand/or system alerts occurs when the heart rate returns to theapproximate starting heart rate and/or a target value. Further, allsystems alerts and/or therapies may occur as independent events and/orexamples. For example, nth system alert event 1514 alert may be thefirst system alert in a specific example. In other words, no otherevents and/or therapies occurred before nth system alert event 1514.Therefore, nth system alert event 1514 becomes the first system alert.In addition, one or more warnings may be transmitted to the patient, acaregiver, a doctor, a medical professional, and/or logged.

In regards to FIGS. 11-15 as related to this disclosure, the systems,devices, and/or methods may use a base line heart rate for the patient(e.g., a specific patient Bob, a general patient John Doe with a firsthealth condition, a first age, etc.) over a first time period (e.g. oneweek, one month, one year, etc.), 50 percentile of all measured heartrates, an average of all heart rates, and/or any other method ofdetermine a baseline heart rate. Further, the threshold level may bedetermined based on being the 40 percentile of the baseline, 39percentile of the baseline, 38 percentile of the baseline, . . . , 10percentile of the baseline, . . . , etc. In addition, the thresholdlevel may be determined based on being the 75 percentile of thebaseline, 76 percentile of the baseline, 77 percentile of the baseline,. . . , 90 percentile of the baseline, . . . , 99 percentile of thebaseline, . . . , etc. In one example, the threshold value may be the 75percentile of every recorded heart rate data. In another example, theoscillation does not matter whether the heart rate change is in anincreasing direction or a decreasing direction. In various examples, thesystems, devices, and/or method may reduce an amplitude of change (e.g.,damping the change in heart rate) to enhance system performance and/orto reduce side effects. In addition, the determination of one or moreside effects may initiate a reduction in therapy, a stoppage of therapy,a modification of therapy (e.g., changing a therapy that reduces heartrate to another therapy that increases heart rate), one or morewarnings, and/or one or more logging of data.

In FIG. 16, a flowchart of a therapy procedure is shown, according toone embodiment. A method 1600 includes obtaining one or more data pointsand/or characteristics relating to heart rate of a patient (step 1602).The method 1600 may also include determining a monitored value based onethe obtained one or more data points and/or characteristics relating tothe heart rate (step 1604). The method 1600 may further compare themonitored value to one or more threshold values (step 1606). The method1600 may via one or more processors (of a medical device(s) and/ormedical device system) determine whether a triggering event has occurred(step 1608). If no triggering event has occurred, then the method 1600moves back to step 1602. If a triggering event has occurred, then themethod 1600 may determine via one or more processors (of a medicaldevice(s) and/or medical device system) whether an action whichincreases heart rate should be implemented (step 1610). If an actionwhich increases heart rate should be implemented, then the method 1600may increase a sympathetic tone via one or more actions and/or decreasea parasympathetic tone via one or more actions and/or implement anotheraction which increases heart rate (step 1612). After the implements ofone or more actions, the method 1600 returns to step 1602. If an actionwhich increases heart rate should not be implemented, then the method1600 may determine via one or more processors (of a medical device(s)and/or medical device system) whether an action which decreases heartrate should be implemented (step 1614). If an action which decreasesheart rate should be implemented, then the method 1600 may decrease asympathetic tone via one or more actions and/or increase aparasympathetic tone via one or more actions and/or implement anotheraction which decreases heart rate (step 1616). After the implements ofone or more actions, the method 1600 returns to step 1602.

In one embodiment, a system for treating a medical condition in apatient includes: a sensor for sensing at least one body data stream; aheart rate unit capable of determining a heart rate of the patient basedon the at least one body data stream; and a logic unit configured viaone or more processors to compare a monitored value which is determinedbased on one or more data points relating to the heart rate to one ormore threshold values, the logic unit further configured to determine atriggering event based on the comparison. Further, the one or moreprocessors may initiate one or more actions to change the heart rate ofthe patient based on the determination of the triggering event.

In another example, the system includes at least one electrode coupledto a vagus nerve of the patient and a programmable electrical signalgenerator. In another example, the one or more processors may increase asympathetic tone to increase the heart rate of the patient. In anotherexample, the one or more processors may decrease a parasympathetic toneto increase the heart rate of the patient. In another example, the oneor more processors may decrease a sympathetic tone to decrease the heartrate of the patient. In another example, the one or more processors mayincrease a parasympathetic tone to decrease the heart rate of thepatient. In another example, the system includes a seizure detectionunit which analyzes the at least one body data stream to determine anepileptic seizure status. In another example, the system includes atleast one electrode coupled to a vagus nerve of the patient and aprogrammable electrical signal generator. Further, the one or moreprocessors may apply an electrical signal to the vagus nerve of thepatient based on a determination that a seizure is characterized by adecrease in the heart rate of the patient where the electrical signal isapplied to block action potential conduction on the vagus nerve.

In another embodiment, a system for treating a medical condition in apatient, includes: a sensor for sensing at least one body data stream;at least one electrode coupled to a vagus nerve of the patient; aprogrammable electrical signal generator; a heart rate unit capable ofdetermining a heart rate of the patient based on the at least one bodydata stream; and a logic unit configured via one or more processors tocompare a monitored value which is determined based on one or more datapoints relating to the heart rate to one or more threshold values, thelogic unit further configured to determine a triggering event based onthe comparison. Further, the one or more processors may initiate one ormore actions to change the heart rate of the patient based on thedetermination of the triggering event.

In another example, the one or more processors may increase asympathetic tone to increase the heart rate of the patient based on afirst triggering event. Further, the one or more processors may decreasea sympathetic tone to decrease the heart rate of the patient based on asecond triggering event. Further, the one or more processors maydecrease a parasympathetic tone to increase the heart rate of thepatient based on a third triggering event. Further, the one or moreprocessors may increase a parasympathetic tone to decrease the heartrate of the patient based on a fourth triggering event.

In another example, the one or more processors may increase thesympathetic tone to increase the heart rate of the patient based on asecond triggering event. Further, the one or more processors mayincrease the sympathetic tone to increase the heart rate of the patientbased on a third triggering event. Further, the one or more processorsincrease the sympathetic tone to increase the heart rate of the patientbased on an nth triggering event.

In another example, the one or more processors decrease a sympathetictone to decrease the heart rate of the patient based on a firsttriggering event. Further, the one or more processors decrease thesympathetic tone to decrease the heart rate of the patient based on asecond triggering event. Further, the one or more processors maydecrease the sympathetic tone to decrease the heart rate of the patientbased on a third triggering event. In addition, the one or moreprocessors decrease the sympathetic tone to decrease the heart rate ofthe patient based on an nth triggering event.

Cardio-protection in epilepsy is a rapidly growing field of vitalimportance. In this disclosure, systems, devices, and/or method ofprotecting the heart from standstill or fatal arhythmias are disclosed.Further in this disclosure, systems, devices, and/or methods ofautomated detections, warnings, reportings, treatments, controls and/orany combination thereof of ictal and peri-ictal chronotropic instabilityare shown.

In FIG. 17, a graph shows monotonic increase and decrease in heart rate.In FIG. 17, a first triggering event, a first warning event, and/or afirst therapy event 1702 are shown. Further, a second triggering event1704, a second warning event, and/or a second therapy event 1704 areshown. In addition, an Nth triggering event, an Nth warning event,and/or an Nth therapy event 1706 are shown. In FIG. 18, the heart rateof the patient increases which is followed by a decrease in heart rate,then an increase heart rate and a final decrease in heart rate. In thisexample, the first drop in heart rate crossed downwardly the detectionthreshold which would have temporarily disabled the warning system andthe delivery of the therapy. While the first peak was not temporallycorrelated with paroxysmal activity on any of the intra-cranialelectrodes used in this patient, it is likely that the first increase inheart rate was caused by epileptic discharges from a brain site that wasnot being investigated. In this example, the x-axis is time in hours andthe y-axis is heart beats per minute. In this example, an electrographiconset in the brain 1810 is shown and an electrographic termination inthe brain 1812 is shown.

In FIG. 19, a change in ictal heart rate is shown. In this example, thedrop in heart rate during the seizure, is even more prominent that theone depicted in FIGS. 17-18, as it is below the interictal baseline. Itshould be noted that the oscillations in heart rate during thepost-ictal period are indicative of cardiac instability. In thisexample, a seizure onset point 1910 and a seizure termination point 1912are shown.

In FIG. 20, large amplitude tachycardia cycles occurringquasi-periodically after termination of paroxysmal activity recordedwith intra-cranial electrodes. While the mechanisms responsible forthese oscillations are unknown, the probability that they are epilepticin nature cannot be excluded, since electrographic and imaging data usedto guide intra-cranial electrode placement pointed to the existence ofonly one epileptogenic site.

In FIG. 21, small amplitude continuous quasi-periodic oscillationspreceding and following a seizure recorded with intra-cranial electrodes(same patient as FIG. 20). In various embodiments, ictal and peri-ictalcardiac instability are shown. The mechanisms leading to SUDEP have notbeen elucidated, in part due to the inability to record data during thecritical events that culminate in cardiac fibrillation or in standstill(or in respiratory arrest). In this example, a first triggering event, afirst warning event, and/or a first therapy event 2102 are shown.Further, an Nth triggering event, an Nth warning event, and/or an Nththerapy event 2104 are shown.

The data obtained in intractable epileptics undergoing epilepsy surgeryevaluation not only supports a cardiac mechanism (of course, not at theexclusion of catastrophic respiratory failure) but more specificallypoints to chronotropic instability as backdrop against which, lethalarrhythmias or cardiac standstill may ensue. Moreover, the instabilityis not restricted to the ictal period but, in certain cases, precedesand/or follows it for several minutes. FIGS. 17-21 illustrate thespectrum of instability in intractable epileptics. This phenomenon isreferred herein to as Ictal and Pre-Ictal Chronotropic Instability.

The challenges that for accurate quantification and delivery ofefficacious therapies, ictal chronotropic instability poses, wereaddressed and strategies to manage them are outlined. Here, theattention is focused on Ictal and Pre-Ictal Chronotropic Instability, amore prolonged and serious pathological phenomenon in intractableepileptics and on the vital issues of cardio-protection.

The aim of this disclosure is to contingently and adaptively dampenbased on the slope, amplitude, duration and “direction” (positive ornegative chronotropic and its magnitude relative to an adaptivebaseline/reference heart rate) the heart oscillations present before,during or after epileptic seizures.

While several embodiments may be envisioned, on embodiment (forefficacy, practicality and cost-effectiveness) is to electricallystimulate/activate the trunk or a branch of the right vagus nerve in thecase of elevations in heart (to reduce the heart rate, when there aremore than 2 consecutive oscillations/cycles or 1 that is large andprolonged. The intensity and duration of stimulation as well as otherparameters are determined by the slope, amplitude and duration of theoscillations, while ensuring adequate blood perfusion to all organs. Inthe case of negative chronotropic effects (decreases in heart rate) thetrunk or a branch of the right vagus nerve may be “blocked” usingcertain electrical stimulation techniques or through cooling; the effectof this intervention is to increase heart rate.

In one embodiment, the “height” of the oscillation is the only featureconsidered. While obviously important, this embodiment does not takeinto consideration a possibly more important feature: the rate at whichthe oscillation occurs: the consequences of waiting to intervene untilan oscillation reaches a certain height (e.g., 120 bpm) are different ifit takes, 30 seconds for the heart rate to reach the value than if ittakes 2 seconds to reach the value. Estimating the rate of change of theheart rate, provides life-saving information. Another aspect is theinter-maxima or inter-minima interval between oscillations. Having heartrate oscillation occur every 2-3 seconds is much more serious than every1-2 hours. In one example, one benefit may be that the window to act islengthened which can save lives. In one embodiment, a system fortreating a medical condition in a patient includes: a sensor for sensingat least one body data stream; a heart rate unit which determines aheart rate and a heart rate oscillation of the patient based on the atleast one body data stream; and a logic unit which compares via one ormore processors a monitored value which is determined based on one ormore data points relating to the heart rate and to the heart rateoscillation to a threshold value, the logic unit determines a triggeringevent based on the comparison where the one or more processors initiateone or more actions to change the heart rate of the patient based on thedetermination of the triggering event.

In another example, the system includes at least one electrode coupledto a vagus nerve of the patient and a programmable electrical signalgenerator. Further, the one or more processors may increase asympathetic tone to increase the heart rate of the patient. In anotherexample, the one or more processors may decrease a parasympathetic toneto increase the heart rate of the patient. In another example, the oneor more processors may decrease a sympathetic tone to decrease the heartrate of the patient. Further, the one or more processors may increase aparasympathetic tone to decrease the heart rate of the patient. Inaddition, the system may include a seizure detection unit which analyzesthe at least one body data stream to determine an epileptic seizurestatus. The system may include at least one electrode coupled to a vagusnerve of the patient and a programmable electrical signal generatorwhere the one or more processors apply an electrical signal to the vagusnerve of the patient based on a determination that a seizure ischaracterized by a decrease in the heart rate of the patient and wherethe electrical signal is applied to block action potential conduction onthe vagus nerve. In addition, the heart unit may determine aninter-maxima interval and an inter-minima interval between a firstoscillation and a second oscillation. Further, the logic unit maycompare the inter-maxima interval and the inter-minima interval to aninterval threshold. In addition, the one or more processors may initiateone or more actions based on the interval threshold being reached.

The particular embodiments disclosed above are illustrative only as thedisclosure may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown other than as describedin the claims below. It is, therefore, evident that the particularembodiments disclosed above may be altered or modified and all suchvariations are considered within the scope and spirit of the disclosure.Accordingly, the protection sought herein is as set forth in the claimsbelow. In addition, all examples, embodiments, and/or elements may becombined in any manner that are disclosed in this document. In otherwords, an element from a first example (paragraph [0088]) can becombined with any other element, such as, a second element from an Nthexample (paragraph [0163]). For brevity, all these examples are notwritten out but are part of this document.

Embodiments disclosed herein provide for detecting an epileptic seizurebased upon an ictal component or content of a body signal value of apatient. The ictal component may be determined based upon the bodysignal value, a reference value of the body signal, and a work level ofthe patient. One or more body signals of a patient may be acquired in atime series, from which a current body index value is determined and awork level of the patient may be determined based on the body indexvalue relative to one of a body index reference value, a temporalfiducial or an activity level. The ictal component of the current bodyindex value may be determined based upon the work level, as well as thecurrent body signal value and the reference value. The magnitude of theictal component may then be used to determine whether or not anepileptic seizure has occurred. If a seizure has occurred, a seizuredetection may be issued. In response to issuing the seizure detection, aresponsive action may be taken. The responsive action may includeproviding a warning, logging the epileptic event, providing a therapy,and/or providing a warning.

More information regarding automated assessments of disease states,comorbidities, and the like may be found in other patent applicationsassigned to Flint Hills Scientific, LLC or Cyberonics, Inc., such as,U.S. Ser. No. 12/816,348, filed Jun. 15, 2010; and U.S. Ser. No.12/816,357, filed Jun. 15, 2010. Each of the patent applicationsidentified in this paragraph is hereby incorporated herein by reference.

More information regarding automated assessments of therapies may befound in other patent applications assigned to Flint Hills Scientific,LLC or Cyberonics, Inc., such as, U.S. Ser. No. 12/729,093, filed Mar.22, 2010; U.S. Ser. No. 13/280,178, filed Oct. 24, 2011; U.S. Ser. No.13/308,913, filed Dec. 1, 2011; and U.S. Ser. No. 13/472,365, filed May15, 2012. Each of the patent applications identified in this paragraphis hereby incorporated herein by reference.

More information regarding the detection of abnormal brain activity,such as seizures, identifying brain locations susceptible to spread ofthe abnormal brain activity, and treating the susceptible brainlocations may be found in other patent applications assigned to FlintHills Scientific, L.L.C., or Cyberonics, Inc., such as, U.S. Ser. No.13/449,166, filed Apr. 17, 2012. Any patent application identified inthis paragraph is hereby incorporated herein by reference.

More information regarding the detection of brain or body activity usingsensors implanted in proximity to the base of the skull may be found inother patent applications assigned to Flint Hills Scientific, L.L.C., orCyberonics, Inc., such as, U.S. Ser. No. 13/678,339, filed Nov. 15,2012. Any patent application identified in this paragraph is herebyincorporated herein by reference.

Over the past several decades, medical devices providing electricaltherapies to treat a number of medical conditions have been developedand approved. Examples of these therapies include pacing anddefibrillation of the heart, electrical stimulation of the spinal cordto treat intractable pain, and stimulation of the vagus nerve to treatepilepsy and depression, among others. In many cases, the patient mustbe gradually acclimated to the exogenous electrical therapy, and thetherapy is gradually increased from a very low dosage to a higher,therapeutically-effective dosage. Heretofore, this process has beenperformed manually. For example, an epilepsy patient being treated withvagus nerve stimulation may initially be provided with no stimulationfor the two weeks following implantation of the device to allow thesurgical incision and trauma to heal, after which the physician (orother healthcare provider) may manually program the device to provide arelative low dosage of pulsed electrical therapy, characterized by acurrent magnitude of 0.1 milliamps (mA)), a pulse width of 0.25milliseconds, a pulse frequency of 30 Hz, an on-time of 30 seconds, andan off-time of 300 seconds. This initial therapy dosage level may be toolow to provide a therapeutic benefit to the patient. Accordingly, thephysician may thereafter manually reprogram the patient every 2-4 weeks,to gradually increase the current magnitude in a number of steps toreach a therapeutically-effective, safe, and tolerable dosage level,e.g., from 0.1 mA to 0.5 mA, then to 0.75 mA, 1.0 mA, 1.25 mA, 1.5 mA,1.75 mA, and finally to 2.0 mA. Such adjustments, referred to herein astherapy titration as the electrical therapy is gradually increased totherapeutically-effective dosage levels, require the patient to makeadditional office visits at significant cost (in money and time) to boththe patient and the treating healthcare provider. The manual titrationprocess may in many cases delay the patient receiving a therapeuticbenefit for weeks or months.

Embodiments disclosed herein provide for programming a medical device toimplement an electrical therapy following implantation of the device,and to automatically titrate at least one parameter defining theelectrical therapy from a first value to a target value. Byautomatically titrating one or more parameters of the electricaltherapy, the patient may be more effectively, more quickly, and morecost-effectively acclimated to the therapy, and may be titrated to atherapeutically-effective dosage of the electrical therapy faster andwith less pain and discomfort. The titration may involve increasing ordecreasing electrical therapy parameters, and may comprise adjusting oneor more parameters (e.g., current (or voltage) amplitude, frequency,pulse width, on-time, off-time, and/or duty cycle) defining the therapyby incremental changes from the first value to the target value. Theadjustments to the one or more parameters may be periodic, aperiodic, orcontingent. In one embodiment, contingent adjustment refers to anadjustment that is automatically initiated, but which requires a user torespond to a prompt before the adjustment is implemented in the therapy.In one embodiment, changes may be manual or automated or in response toinput from a person. In some embodiments, two or more parameters may beautomatically titrated from respective first values to respective targetvalues. In some embodiments, undesirable side effects may be detectedand used to return one or more automatically titrated parameters to aprior value before resuming the titration to the target value. By usingside effects (such as pain, discomfort, or changes in one or more bodyindices such as heart rate) to indicate a lack of tolerance and/orsafety of a particular titration step, titration may be automaticallyadjusted to rapidly, safely and comfortably titrate the patient totherapeutically-effective, tolerable, and safe therapy dosage levels.

In some embodiments, the medical device may be programmed to establish afirst target value for a first electrical therapy parameter. The firstelectrical therapy parameter may be one or more of the previously notedparameters defining or characterizing the electrical therapy. In someembodiments, the medical device may be programmed to establish a firsttarget value for more than a first electrical therapy parameter, e.g.,the device may be programmed to establish first values and/or targetvalues for a first, a second, a third, and an nth electrical therapyparameter. The automated titration of multiple parameters may besequential, simultaneous, and/or partially overlapping, and may betailored to address one or more of efficacy, safety, and tolerability,which may be separately impacted by changes associated with each of oneor more of the individual parameters.

Embodiments of the invention also involve programming at least onetitration parameter for automatically adjusting the first (and/orsecond, third, etc.) electrical therapy parameter from the first valueto the target value. The titration parameter may be selected from atitration time period, a titration step interval, a titration stepmagnitude, and/or a titration rate. The titration time period is thetime period in which an electrical parameter is to be titrated from theinitial value to the target value, e.g., 2 weeks. In some embodiments,different titration time periods may be set for each of a plurality ofparameters characterizing the electrical signal, e.g., the current maybe titrated to the target value over a period of 2 weeks, while thepulse amplitude may be titrated to the target value over one week. Thetitration step interval is a time interval at which at least onetitration adjustment step is made. In some embodiments, all of thetitration steps are made at the same titration step interval, while inother embodiments, only the initial titration step interval is provided,and subsequent step intervals are determined based upon a titrationfunction describing how the titration is to occur (e.g., uniformly ornon-uniformly). The titration step magnitude is the magnitude of thechange made to at least one adjustment of an electrical parameter. Forexample, current adjustments may be made with a titration step magnitudeof 0.1 mA, with each new automatic current adjustment comprising a 0.1mA increase over the prior value. In some embodiments, titration stepmagnitudes may be specified for a plurality of electrical parameters(e.g., a current titration step magnitude of 0.1 mA, and a pulse widthstep magnitude of 0.05 msec). In some embodiments, all of the titrationsteps for a given electrical parameter are made at the same titrationstep magnitude, while in other embodiments, only the initial titrationstep interval is provided, and subsequent step intervals are determinedbased upon a titration function describing how the titration is to occur(e.g., uniformly or non-uniformly). In one embodiment, the automatedtitration process may occur at various different scales as a function oftitration rate. By way of a first example, the rate at which the targetvalue is reached or approached may be equivalent or comparable to thetitration step magnitude divided by the titration time interval. By wayof a second example, the rate at which a parameter is changed at a stepof the titration.

The titration adjustments may be made according to a titration functiondescribing how the titration steps are to be implemented. In oneembodiment, the titration function may be a linear stepwise function inwhich uniform titration step magnitude changes are made at uniformtitration step intervals. In other embodiments, the titration functionmay be implemented as a non-linear stepwise function, a stepwiseapproximation of a polynomial, a continuous function, or a mixedstepwise and continuous function. In an example of a non-linearfunction, one or more of the titration step interval and the titrationstep magnitude may be non-linear, and may be, for example, a parabolicor higher-order polynomial.

Non-limiting examples of various titration functions are shown in FIGS.11-12. FIG. 11 shows that various parameters may vary according todifferent functions, e.g., for the functions shown in solid lines, thecurrent (in mA) may have a convex shape over the course of thetitration, and the frequency (in Hz) may have a concave shape. Foranother example, for the functions shown in dashed lines, both currentand frequency may have the same general shape (e.g., concave) over thecourse of titration, but one may reach a final value faster than theother. FIG. 12 shows an example of a parabolic function, e.g., y=−x2 forx=[−5, 0].

In some embodiments, a titration function may be self-similar or fractal(i.e., each step may have the same shape as the overall function). Also,although FIGS. 11-12 show smooth parabolic functions, a parabola (orother smooth shape) may be approximated by a series of relatively smallsteps. As the person of ordinary skill in the art, having the benefit ofthe present disclosure, will understand, other functions than thoseshown in FIGS. 11-12 may be used.

The titration function may be programmably selected by a healthcareprovider or may be a predetermined function such as a linear function.In some embodiments, the titration function may further be influenced byadditional factors such as the patient's age, health status, gender, theseverity of the disorder being treated (e.g., seizure type, frequencyand severity in patients with epilepsy), the patient's tolerance toadverse events, the patient's tolerance to pain, among other relevantfactors.

In some embodiments, the titration function may be interrupted ormodified by the occurrence of one or more events, such as one or moreside effects, patient tolerance, patient safety, or patient diseasestate, among others. For example, the titration function as initiallyprogrammed may be automatically adjusted to accelerate, slow down, ortemporarily suspend or reverse the titration process based upon one ormore body signal(s). The one or more body signals may be analyzed by themedical device and an automated adjustment of the titration process maybe performed by, e.g., lowering a parameter value that results inundesired side effects such as discomfort, pain, respiratory effects(e.g., dyspnea), voice alteration, changes in heart rate, etc., to allowthe patient additional time to accommodate to the previous stimulationdosage before resuming the titration process. In addition, feedback fromexternal sources, e.g., manual input by the patient or a caregiver may,also be used to reverse, slow down, or accelerate the titrating of thetherapy.

The titration of the therapy may be implemented by initiating theelectrical therapy with the one or more parameters to be titrated set attheir respective initial values. The therapy may thereafter be titratedby automatically adjusting the one or more electrical therapy parametersbased upon the programmed one or more titration parameters (e.g., thetitration time period, titration step period, titration step magnitude,and/or titration rate) and the titration function.

As an example, a health care provider may program a medical device toprovide an electrical therapy in which a first parameter such aselectrical pulse current increases from an initial value of 0 mA to atarget value of 2.0 mA. The therapy may be automatically titrated fromthe initial value to the target value based on the titration time periodaccording to the titration function. In one embodiment, various stepsbetween the initial value and the target value may be made such that thetitration process causes the therapy signal to have a specific value ateach of these intermediate steps until the target value is achieved.That is, the automatic titration feature may “ramp up” a parameterdefining the electrical therapy by increasing the parameter in smallincrements over a programmed titration time period. In a particularembodiment, the incremental increase may be implemented once each dayover a programmed time period selected from one day to 60 days, and mayinclude two days, three days, four days, five days, one week, ten days,two weeks, three weeks, four weeks, or any other period from 2-60 days.In one embodiment, titration may be adjusted in view of one or more ofpatient input, body signals, or brain evoked responses.

In some embodiments, a user may not need to explicitly program atitration time period. Instead, the user may program a titration stepmagnitude and a titration step interval. According to such embodiments,the electrical therapy is initiated with the therapy parameter at afirst value, and the value is iteratively increased by the titrationstep magnitude after the lapse of each titration step interval. Forexample, an electrical therapy used to provide vagus nerve stimulationtherapy to a patient may be increased by 0.1 mA (or other titration stepmagnitude) each day (or other titration step interval) until the targetvalue is reached. The patient, physician or healthcare provider may besent a message when the target dosage is reached according to someembodiments.

In other embodiments, the titration of the therapy may be automaticallyor manually altered. For example, in some embodiments, body data fromthe patient may be used to evaluate one or more effects of the automatictherapy titration. Based on the one or more effects of the therapy, thetitration of the therapy may be altered. In another embodiment, ifefficacy is detected (as determined, e.g., from body data) during thetitration process, then further titrating of the therapy may besuspended. Alternatively, if side effects of the therapy are found, thetitration may be suspended or reversed until further interaction with ahealthcare provider. In some embodiments, the titration process may bereversed upon a first detection of a side effect, and after resuming thetitration process, detection of a second or a third side effect mayresult in suspension of further automatic titration of the electricaltherapy until the patient's physician programs the medical device toresume the titration, in which case an alert may be sent to thephysician or other caregiver. In a further embodiment, if no adverseeffects of the therapy are noted, the titration of the therapy may beaccelerated to reach the target value sooner than a programmed titrationtime period. The adjustment of the titrating process may be an automatediterative process, wherein adjustments to the titrating steps may bealtered based upon body data analysis during each delivery of therapy.

FIG. 22 shows a stylized block diagram representation of a medicaldevice system, according to some embodiments of the present disclosure.The medical device system 2251 may comprise a medical device 2200,electrode(s) 2212, lead(s) 2211 coupling the electrode(s) 2212 to themedical device 2200, sensor(s) 2214, and lead(s) 2213 coupling thesensor(s) 2214 to the medical device 2200. The electrode(s) 2212 may beconfigured to deliver an electrical therapy defined by a plurality ofparameters to a patient. The sensor(s) 2214 may be configured to collectbody data relating to any body data stream of the patient, which mayinclude as non-limiting examples one or more of the patient's cardiacsignal (e.g., heart rate, heart rate variability), respiratory signal(e.g., respiratory rate, end tidal volume, respiratory ratevariability), blood oxygen saturation, blood oxygen saturationvariability, discomfort level, gastro-intestinal activity, shortness ofbreath, or vocal cord function. The medical device system 2251 includesa programmer 2252 which may be used to program the medical device 2200,which in some embodiments is an implantable medical device (IMD), apartially implantable medical device, or a portable external medicaldevice with one or more parameters characterizing the electrical therapyand one or more titration parameters to automatically titrate the one ormore parameters from a first value to a target value. In someembodiments, a patient (manual) input device 2216 may be coupled to themedical device 2200 by lead(s) 2215 or by a wireless coupling (notshown), and may be used to provide an input (which may be a manual inputor an automatic input from, e.g., an accelerometer other sensing deviceincorporated in the patient input device 2216) from the patient.

Various components of the medical device 2200, such as controller 2210,processor 2215, memory 2217, power supply 2230, and communication unit2240 have been described in other patent applications assigned to FlintHills Scientific, LLC or Cyberonics, Inc., such as, U.S. Ser. No.12/770,562, filed Apr. 29, 2010; U.S. Ser. No. 12/771,727, filed Apr.30, 2010; U.S. Ser. No. 12/771,783, filed Apr. 30, 2010; U.S. Ser. No.12/884,051, filed Sep. 16, 2010; U.S. Ser. No. 13/554,367, filed Jul.20, 2012; U.S. Ser. No. 13/554,694, filed Jul. 20, 2012; U.S. Ser. No.13/559,116, filed Jul. 26, 2012; and U.S. Ser. No. 13/598,339, filedAug. 29, 2012; U.S. Ser. No. 12/896,525, filed Oct. 1, 2010, now U.S.Pat. No. 8,337,404, issued Dec. 25, 2012; U.S. Ser. No. 13/098,262,filed Apr. 29, 2011; U.S. Ser. No. 13/288,886, filed Nov. 3, 2011; U.S.Ser. No. 13/554,367, filed Jul. 20, 2012; U.S. Ser. No. 13/554,694,filed Jul. 20, 2012; U.S. Ser. No. 13/559,116, filed Jul. 26, 2012; andU.S. Ser. No. 13/598,339, filed Aug. 29, 2012. Each of the patentapplications identified in this paragraph is hereby incorporated hereinby reference.

The medical device 2200 may comprise an electrical therapy module 2250to generate an electrical therapy signal that may be provided as anelectrical therapy to a target body structure such as a cranial nerve orbrain tissue via electrodes 2212. The electrical therapy signal may becharacterized by a plurality of parameters, e.g., an amplitude, a pulsewidth, a pulse frequency, a signal on-time, or a signal off-time, amongothers. The electrical therapy module 2250 may be configured to deliveran electrical therapy signal having a low initial or first value of oneor more parameters upon initiation of the treatment regimen. Thetreatment regimen may be initiated after implantation of electrode(s)2212, medical device 2200, or other components of the medical devicesystem 2251. Alternatively or in addition, the therapy may be initiatedas part of a “reboot” or “reset” of a previously suspended therapy. Inone embodiment, the electrical therapy signal may be programmed alongwith one or more titration parameters to titrate an electrical currentsetting for electrical pulses applied to a target structure from a firstvalue (e.g., 0 mA or 0.1 mA) to a target value for providing therapy(e.g., 2.5 mA).

The treatment regimen may be configured to treat epilepsy, depression,pain, congestive heart failure, traumatic brain injury, or obesity,among other ailments known to persons of skill in the art to be amenableto treatment by electrical therapy of the body, e.g., of neuralstructures, e.g., of the brain, spinal cord, or a cranial nerve, e.g.,the vagus nerve.

The medical device 2200 may also comprise a body data module 2270. Thebody data module 2270 is capable of acquiring signal(s) relating to apatient's body data, processing and analyzing the signals to assess theeffects (beneficial or deleterious) of the therapy on the patient. Thebody data module 2270 may also be configured to determine one of a timeseries of body data values or body index values based upon the timeseries. Such a time series of body index values may comprise at leastone of an instantaneous heart rate (HR), a heart rate variability (HRV),an instantaneous respiratory rate (RR), an instantaneous blood pressure(BP), an instantaneous blood oxygen saturation (02S) value, a bloodoxygen saturation variability, or vocal cord function, among others.Body data module 2270 is shown in FIG. 23 and accompanying descriptionbelow.

In one embodiment, the body data module 2270 may comprise an evokedresponse unit 2272. The evoked response unit 2272 may be configured toapply a signal to a body tissue and determine what response, if any, isevoked in the tissue by the signal. For example, the evoked responseunit 2272 may comprise a stimulator 2274 configured to apply a signalexpected to evoke a response, and an interpreter 2276 configured todetermine what response, if any, was evoked by the signal.

In one embodiment, the evoked response unit 2272 may be a vagus evokedresponse unit, i.e., a unit configured to acquire data from the vagusnerve relating to responses evoked on a body tissue (e.g., a vagusnerve, a heart, or a brain or a region thereof) by an electricalstimulation or to acquire EEG or ECoG data. Alternatively or inaddition, the evoked response unit 2272 may be a voice evoked responseunit, i.e., a unit configured to acquire data from the patient's bodyrelating to responses evoked on the vocal cords and/or other vocalapparatus by an electrical stimulation or other therapy modality. Forexample, vagus nerve stimulation may interfere with a patient's vocalcord function, e.g., by rendering the voice hoarse or husky, and anevoked response unit 2272 according to this embodiment may gather andanalyze data relating to such evoked responses.

The medical device 2200 may comprise a therapy titration module 2260configured to titrate one or more electrical therapy parameters to atarget value according to a titration function. The titration mayinvolve decreasing the therapy parameters at certain times in responseto the occurrence of an adverse event. (As used herein, “adverse event”refers to side effects and/or other undesirable events). In someembodiments, the titration is continued until one or more of atolerable, a safe, an efficacious, and/or a target electrical parametervalue is achieved. In other words, the target dosage may be eithertolerable, efficacious or both. In some embodiments, the programmedtarget value for a titration parameter may be altered to a lower orhigher value based upon one or more of a measured level of efficacy (orlack of efficacy) or the emergence of side effects.

The titration module 2260 may comprise a titration control unit 2265configured to determine and implement the titration function. In someembodiments, the titration function may be determined by looking upinformation from a titration parameter module 2262. In some embodiments,titration parameters for performing the titration may also be programmedinto the medical device 2200 from an external programming device 2252 bya physician, and stored into memory. The titration parameters mayinclude one or more of the titration time period, the titration stepinterval, the titration step magnitude, the titration rate, and one ormore other parameters defining the titration function.

As shown in FIG. 24, in some embodiments, the therapy titration module2260 may comprise a titration parameter data processing unit 2430 toprocess data to implement the titration of the one or more electricaltherapy parameters; a titration algorithm unit 2420 for providinginstructions relating to titrating of one or more electrical parametersof the electrical therapy signal; the titration control unit 2265 toreceive data from at least one of the titration parameter dataprocessing unit 2430, the titration algorithm unit 2420, and thetitration parameters unit 2262. Therapy titration unit 2260 may furthercomprise an electrical therapy parameter unit 2440, operatively coupledto the titration control unit 2265, to provide one or more values of theelectrical therapy parameters to be titrated to the electrical therapymodule 2250, such as one or more initial (or first) and target valuesfor the electrical parameters to be titrated, as well as values forother parameter that are not intended to be titrated. In someembodiments, the titration parameter data processing unit 2430 may beconfigured to receive data from a dynamic adjustment unit 2268,described below. The titration parameter data processing unit 2430 maybe capable of processing data to determine a titration protocol orfunction. The titration function may be defined by one or moreparameters that determine how the electrical therapy parameters are tobe titrated to the target value and may determine one or more titrationperiods, titration step intervals, titration step magnitudes, and/ortitration step rates.

The therapy titration module 2260 may further comprise a dynamicadjustment unit 2268 configured to adjust one or more electricalparameters and/or titration parameters based on the feedback data from,e.g., sensors 2214 and/or feedback module 2280. The dynamic adjustmentunit 2268 may accelerate, slow down, suspend, or resume the programmedtitration process according to body data received from the patient. Insome embodiments, the dynamic adjustment unit 2268 may be used todetermine one or more of a measure of efficacy of the therapy (toidentify and/or quantify whether or not the electrical therapy isefficacious) or a side effect of the therapy, and to use such measure ofefficacy, lack of efficacy, or side effects, to cause titration controlunit 2265 to accelerate, interrupt or suspend, reduce, or resume thetherapy titration process. In some embodiments, the dynamic adjustmentunit 2268 may cause titration control unit 2265 to adjust the one ormore electrical therapy parameters to slow the titration of the one ormore electrical therapy parameters to their respective target values,while in others the titration function may be adjusted to speed up thetitration to the target value. For example, if the feedback dataindicates that the patient suffered an adverse reaction to theelectrical therapy, the dynamic adjustment unit 2268 may increase thetitration step interval to slow titration of the electrical therapyparameter(s), or it may reduce one or more electrical therapy parametersbeing titrated to the most recent value not associated with an adverseeffect. Doing so may eliminate or reduce a side effect, and allow thepatient additional time to accommodate to a particular titration step.As another example, if the feedback data indicates that the patient didnot suffer an adverse reaction to the treatment and the treatment lackssufficient efficacy, the dynamic adjustment unit 2268 may reduce atitration step interval to prompt a faster titration of the therapy. Inthis manner, the dynamic adjustment unit 2268 and the therapy titrationmodule 160 are capable of improving safety and efficacy of therapy.

Returning to FIG. 22, the medical device 2200 may comprise a feedbackmodule 2280 configured to provide feedback data from the patient's body,wherein the feedback comprises at least one of body data (e.g., thatprovided by body data module 2270) or a manual input from the patient(e.g., provided by patient input device 2216). The feedback module 2280may provide feedback relating to the efficacy of the treatment, thesafety of the treatment, one or more body reactions to the treatment,etc. The feedback module 2280 may also provide external feedbackreceived from the patient or a medical professional. Information fromthe feedback module 2280 may be used to adjust the titration of thetherapy

Turning now to FIG. 25, the dynamic adjustment unit 2268 may alsocomprise a parameter magnitude adjustment unit 2530, a timing module2520, an efficacy module 2550, an adverse effect module 2560, and atitration override module 2540. The parameter magnitude adjustment unit2530 may be configured to provide data relating to the magnitude of oneor more adjustments to be made to the value of an electrical therapyparameter. The timing module 2520 may be configured for determining thetiming of one or more adjustments to be made to the value of anelectrical therapy parameter to be titrated (e.g., the length of timethe electrical parameter is kept at a particular value, and/or the timesat which the parameter is adjusted to a next value or a previous value).Data from the parameter magnitude adjustment unit 2530 may be utilizedby the timing module 2520 to determine the timing of the adjustments tothe electrical therapy parameters.

The adverse effect module 2560 (which may also be referred to as a sideeffect module) may be configured to determine at least one adverseeffect of the electrical therapy, e.g., an observation that thetreatment regimen is unsafe and/or intolerable. Data from the adverseeffect module 2560 may be used by the parameter magnitude adjustmentunit 2530 and/or timing module 2520 to determine the rate of increasefor titrating one or more parameters of the electrical therapy signal.For example, if the adverse effect module detects that certain parametervalues of the electrical signal, at a certain point in the therapytitration process, cause an adverse event (e.g., pain, vocal problems,sudden drop in blood pressure or heart rate, etc.), the parametermagnitude adjustment unit 2530 may reduce the rate of increase of anelectrical therapy parameter, maintain the current value of theparameter, or may reduce the value of the parameter, to allow theadverse event to resolve. In some embodiments, these actions may betaken for more than one electrical therapy parameter. Further, theadverse effect module 2560 may correlate certain titration adjustmentsto adverse effects and store such data. This data may be used by medicaldevice 2200 to control parameters of future titrations.

In one embodiment, the dynamic adjustment unit 2268 may include anefficacy module 2550 configured to determine at least one body indexcomprising a measure of efficacy of the electrical therapy. The efficacyindex may be determined based at least in part on collected body data oron reports or input from the patient. In some embodiments, the dynamicadjustment unit 2268 may be configured to adjust the value of anelectrical parameter to be titrated based on the one or more efficacyindex values. Depending upon whether the efficacy module 2550 indicatesthat the therapy is efficacious, not efficacious, or is indeterminate,the titration process may be modified (e.g., accelerated, interrupted orsuspended, or reversed, among others). More particularly, data from theefficacy module 2550 regarding the efficacy of the electrical therapymay be used by the parameter magnitude adjustment unit 2530 to makeautomated adjustments to the titration parameter(s), and/or by thetiming module 2520 to change the timing of the adjustments to theparameter(s). As a non-limiting example, if the efficacy data indicatesthat the previously applied treatment was not sufficiently efficaciouswithin a predetermined time period, the electrical therapy signal may bechanged by increasing the magnitude of the adjustment to be made to anelectrical therapy parameter, and/or decreasing the time period requiredbefore the next adjustment is made, in an effort to increase theelectrical therapy dosage provided to the patient. In alternativeembodiments, the efficacy module 2550 may instead be a component ofanother portion of the medical device 2200 rather than the dynamicadjustment unit 2268.

The term “reduce” the value of the electrical parameter is used above inview of the typical situation where the titration of the electricalparameter is from a low initial value to a high target value associated(or expected to be associated) with efficacy. This is generally the casefor amplitude, pulse width, and pulse frequency. An adverse effect mayresult from a titration with too high a step magnitude or step rate, orwith a step implemented too soon (i.e., with a step interval that is tooshort) for the patient to have acclimated to a prior titration increase.In such cases, reducing the value may be appropriate to minimize orreverse the adverse effect. However, some parameters, e.g., signaloff-time, may be titrated from a high initial value to a low targetvalue associated with efficacy. In such situations, increasing the valueof the signal off-time may be appropriate to minimize or reverse theadverse effect, and to allow the patient a longer period of time tobecome habituated or acclimated to a particular titration increase.

The dynamic adjustment unit 2268 may also comprise a titration overridemodule 2540 for overriding the programmed titration of the electricaltherapy parameter(s). For example, based upon a signal from the adverseeffect module or an input from the patient or a healthcare provider, thetitration override module 2540 may override the programmed titration.The overriding of the titration may include suspending a next plannedadjustment to the one or more electrical therapy parameters beingtitrated. Subsequent adjustments to the electrical therapy parameter(s)may be provided according to data generated by one or more of timingmodule 2520, the parameter magnitude adjustment unit 2530, efficacymodule 2550, and adverse effect module 2560. The subsequent adjustmentsmay include stopping a current titration process and implementing adefault titration process, ending the titration process altogether,implementing a slower titration process, implementing titration to ahigher (or lower) final value, etc.

FIG. 23 shows a block diagram depiction of a medical device 2200, inaccordance with one illustrative embodiment of the present invention.FIG. 23 depicts an exemplary implementation of the body data module 2270described above with respect to FIG. 22. The body data module 2270 mayinclude a body data memory 2351 for storing and/or buffering data in thebody data module 2270. The body data memory 2351 may, in someembodiments, be adapted to store body data for logging or reportingpurposes and/or for future body data processing. The body data module2270 may also include one or more body data interfaces 2310. The bodydata interface 2310 may provide an interface for input/output (I/O)communications between the body data module 2270 and body dataunits/modules (e.g., [2360-2370], [2373-2376]) via connection 2380.Connection 2380 may a wired or wireless connection, or a combination ofthe two. The connection 2380 may be a bus-like implementation or mayinclude an individual connection (not shown) for each or some number, ofthe body data unit (e.g., [2360-2370], [2373-2376]). The connection 2380may also include connection elements as would be known to one of skillin the art having the benefit of this disclosure. The specificimplementation of the connection 2380 does not serve to limit otheraspects of various embodiments described herein unless specificallydescribed. In this regard, body data acquisition units/modules 2360,2370, 2373, 2374, 2375 may also include one or more of sensors 2214 andleads 2215 (FIG. 22).

In various embodiments, the body data units may include, but are notlimited to, an autonomic data acquisition unit 2360, a neurologic dataacquisition unit 2370, and endocrine data acquisition unit 2373, ametabolic data acquisition unit 2374 and/or a tissue stress marker dataacquisition unit 2375. In one embodiment, the body data units mayinclude a physical fitness determination unit 2376. In one embodiment,the autonomic data acquisition unit 2360 may include a heartbeat dataacquisition unit 2361 adapted to acquire heart sounds, EKG data, PKGdata, heart echo, apexcardiography and/or the like, a blood pressureacquisition unit 2363, a respiration acquisition unit 2364, a bloodgases acquisition unit 2365, and/or the like. In one embodiment, theneurologic data acquisition unit 2370 may contain a kinetic unit 2366that may comprise an accelerometer unit 2367, an inclinometer unit 2368,and/or the like; the neurologic data acquisition unit 2370 may alsocontain a responsiveness/awareness unit 2369 that may be used todetermine a patient's responsiveness to testing/stimuli and/or apatient's awareness of their surroundings. These lists are notinclusive, and the body data module 2270 may collect additional data notlisted herein, that would become apparent to one of skill in the arthaving the benefit of this disclosure. The body data acquisition units([2360-2370], [2373-2376]) may be adapted to collect, acquire, receiveand/or transmit heart beat data, EKG data, PKG data, heart echo,apexcardiography, heart sound data, blood pressure data, respirationdata, blood gases data, body acceleration data, body incline data and/orthe like.

The body data interface(s) 2310 may include various amplifier(s) 2320,one or more A/D converters 2330 and/or one or more buffers 2340 or othermemory (not shown). In one embodiment, the amplifier(s) 2320 may beadapted to boost incoming and/or outgoing signal strengths for signalssuch as those to/from any body data units/modules (e.g., ([2360-2370],[2373-2376]) or signals to/from other units/modules of the IMD 2200. TheA/D converter(s) 2330 may be adapted to convert analog input signalsfrom body data unit(s)/module(s) (e.g., ([2360-2370], [2373-2376]) intoa digital signal format for processing by controller 2210 (and/orprocessor 2215). Such analog signals may include, but is not limited to,heart beat data, EKG data, PKG data, heart echo, apexcardiography, heartsound data, blood pressure data, respiration data, blood gases data,body acceleration data, body incline data and/or the like. A convertedsignal may also be stored in a buffer(s) 2340, a body data memory 2351,or some other memory internal to the IMD 2200 (e.g., memory 2217) orexternal to the IMD 2200 (e.g., patient input device 2216 or programmer2252). The buffer(s) 2340 may be adapted to buffer and/or store signalsreceived by the body data module 2270 as well as signals to betransmitted by the body data module 2270. In various embodiments, thebuffer(s) 2340 may also be adapted to buffer and/or store signals in thebody data module 2270 as these signals are transmitted betweencomponents of the body data module 2270.

FIG. 26 depicts a stylized depiction of one example of a titration of anelectrical therapy, according to some embodiments herein. In oneembodiment, the illustration in FIG. 26 may represent a titration of afirst electrical therapy parameter, e.g., the current amplitude of thetherapy signal. In alternative embodiments, the illustration of FIG. 26may represent a titration of a plurality of parameters, e.g., acomposite representation of amplitude and pulse width or frequency.Additional but different figures, having different timing and magnitudefor the adjustments, could be provided for a second, third, fourth,etc., parameter to be titrated. Those skilled in the art having benefitof the present disclosure would appreciate that the general principlesof FIG. 26 are applicable to any electrical parameter that may be partof a titration of an electrical therapy of a patient by adjusting theparameter from a first value to a target value.

Starting from a first or initial magnitude shown in FIG. 26, the firstelectrical therapy parameter may be increased by a titration stepmagnitude (dashed line shown in FIG. 26 as being the same for each stepbut which may be different in alternative embodiments) at each of aplurality of titration step intervals (also depicted as uniform in FIG.26 but which may be different in alternative embodiments. The periodfrom the initial time (when the therapy is started) to the time at whichthe target value is reached is the titration time period. From theinitial time to 1st step, the electrical therapy parameter remains atthe first value to allow the patient's body to be acclimated to thetherapy signal at the first value. At the first step, the firstparameter value is increased to a second, higher value (e.g., from 0.1to 0.2 mA), and it remains at that value for the titration stepinterval, at the lapse of which the first parameter value is thenincreased (at the 2nd step) to a 3rd, still higher value. The firstparameter remains at the 3rd value for another titration step interval,at which time (the 3rd step), when the value is raised to a 4th value.After the lapse of another titration step interval, the first parameteris then increased (at the 4th step) to the target value. Therepresentative process illustrated may be made in a greater number ofsteps with smaller titration step magnitudes to improve the patient'sability to tolerate each step. The stepwise process is repeated untilthe target value of the first parameter is reached. The time to targetvalue may be determined by the timing module 2520 (FIG. 25) of thedynamic adjustment module 2270.

FIG. 26 also shows the titration rate on two timescales, e.g., a globaltime scale (dotted line), comparable in value to the sum of thetitration step magnitudes divided by the time to target level, and localtime scales (dashed and dashed-dotted lines), indicating alternativeapproaches to bringing the amplitude up to the level of a next step.

The patient's tolerance for an increase in a titrated parameter may varydepending on the patient's state, e.g., the patient's level ofconsciousness, level of attention, mood, general health, gender, age,etc. Changes in the titration process may be made accordingly. Forexample, if the patient is more tolerant of the increase at night, acurrent setting may be increased at night (e.g., while the patient isasleep) from a lower amplitude to a higher amplitude. Upon awakening,the amplitude may be maintained at the higher amplitude or reduced to anintermediate value if the patient does not tolerate the higher amplitudewhen awake. In this manner, the titrating function may accelerate thepatient's accommodation to the higher amplitude and/or accelerate theoverall titration process.

FIG. 27 illustrates a stylized depiction of one example of a dynamicadjustment of a titration function, according to some embodiments.Again, by way of example, the depicted value along the y-axis of FIG. 27is the first electrical therapy parameter, e.g., current amplitude. Thegeneral principles illustrated, however, are applicable to anyelectrical therapy parameter that may be titrated as part of a therapytitration to an efficacious dosage. In this example, an adverse effect(not shown) is determined to occur sometime after titrating up to the3rd step. As shown, the dynamic adjustment comprises reducing the valueof the first parameter, e.g., current amplitude, to the last knowntolerable value (e.g., the value of the 2nd step), lengthening of theduration of the current tolerable/safe magnitude before the firstparameter is titrated to the next higher magnitude. In one embodiment,subsequent steps may be initiated at the originally programmed stepmagnitude, as illustrated by the series of steps leading to the targetvalue (dashed line), while in alternative embodiments, the dynamicadjustment may also or alternatively comprise decreasing the stepmagnitude to be applied at future titration steps, as shown by theadjusted steps having a smaller magnitude than the earlier (1st, 2nd and3rd) step magnitudes (dotted line).

In embodiments having a reduced step magnitude, a new (greater)titration time period for reaching the target value may be determined.That is, upon detection of an adverse event, the titration stepmagnitude may be reduced for future titration steps resulting in alonger titration time period necessary to reach the target value for theelectrical therapy parameter(s) being titrated. In this manner, a morecomfortable and/or safer titration process may be provided to thepatient.

FIG. 28 illustrates a flowchart representation of a method 2800 forperforming an automated titration of one or more electrical therapyparameters in accordance with some embodiments herein. Parametersdefining an electrical therapy may be programmed (block 2810) into amedical device based upon at least one target value for an electricalparameter to be titrated (e.g., an electrical therapy that the patientcannot immediately tolerate at the dosage associated with the targetvalue). The therapy regimen may be configured to treat one or more ofseveral diseases, such as epilepsy, depression, pain, congestive heartfailure, traumatic brain injury, or obesity.

Programming at 2810 may include providing first value(s) and targetvalue(s) for at least one parameter.

One or more titration parameters characterizing the titration of the oneor more electrical therapy parameters being titrated may be programmedinto the medical device (block 2820). The electrical therapy may beimplemented with the electrical therapy parameters to be titrated havingtheir first or initial values (block 2830). Thereafter, the electricaltherapy may be automatically titrated (block 2840) based on theprogrammed target value(s) of the electrical parameter(s), the titrationparameters, and a titration function. The titration function may includevarious patterns for adjusting the electrical therapy parameter(s),e.g., uniform titration magnitude steps and titration step intervals, ornon-uniform adjustments (e.g., according to a parabolic function, ahigher-order polynomial, etc.).

In some embodiments, the method 2800 may further comprise sending amessage to the patient and/or a caregiver or healthcare provided aphysician when the target value is reached, or when a change to theprogrammed titration has occurred, or when a side effect has beendetected.

FIG. 29 illustrates a flowchart depiction of automatically titrating theelectrical therapy based upon the titration parameters and the titrationfunction (block 2840 of FIG. 28), in accordance with some embodimentsherein. At block 2910, the medical device 2200 may deliver the therapyat the first (initial) values for the electrical therapy parametersprogrammed into the medical device.

As the therapy is delivered, logic in the MD 2200 determines whether ornot the titration step interval has elapsed (block 2920). If so, theelectrical therapy parameter(s) to be titrated are adjusted by thetitration step magnitude (block 2930).

In one embodiment, titration logic in the MD 2200 determines whether ornot an adverse effect has occurred (block 2940). If no adverse event hasoccurred, the logic thereafter checks to determine if the next titrationstep interval has elapsed (block 2950). If the titration step intervalhas not elapsed, the logic continues to check for adverse effects (block2940), and if the titration step interval has elapsed, the logic checksto determine if current value of the electrical signal parameter is thefinal value (block 2960). If the current value is the final value, MD2200 continues to operate the therapy with the parameter at the targetvalue (block 2970), while if the final titration value has not beenreached, the logic again adjusts the electrical therapy by the titrationstep magnitude (block 2930).

If at any point after an adjustment is made (block 2930) an adverseeffect occurs (block 2940), the value of the electrical therapyparameter is reduced to a prior tolerable value (block 2980), e.g., ahighest previously tolerable amplitude. In some embodiments, changes toone or more of the titration step magnitude and the titration stepinterval may also be made as part of block 2980. In alternativeembodiments, the therapy may be suspended rather than continued at areduced stimulation dosage. After the reduction of the electricaltherapy parameter to a lower value (with or without changes to the stepmagnitude and/or interval), the logic then checks to determine if thetitration step interval has elapsed (either as originally programmed oras modified) at step 2990. If the interval has elapsed, the electricaltherapy parameter is adjusted by the titration step magnitude at step2930.

The indications of an adverse effect or event (2940) may be based on oneor more body indices derived from a body signal. Exemplary body indicesinclude one or more of the patient's heart rate, heart rate variability,blood oxygen saturation, respiratory rate, blood oxygen saturationvariability, respiratory rate variability, discomfort, shortness ofbreath, or vocal cord function. Unacceptable changes indicative of alack of patient tolerance may be used to indicate the occurrence of anadverse effect. Alternatively or in addition, a manual input from thepatient or another external source, such as a medical professional, maybe used to indicate an adverse effect. Exemplary manual inputs includebut are not limited to tap sensor inputs, magnetic sensor inputs,manipulation of one or more physical or virtual keys on a handhelddevice, etc.

In some embodiments, the adverse event indication may include a severityof the adverse effect, or to the rate of occurrence of an effect that ata low rate would not be an adverse effect. When adverse events occur,the magnitude of the reduction of the electrical signal parameter and/orchanges to the titration step interval and step magnitude (block 2980)may be based on the type, severity and/or rate of the adverse effect.

In some embodiments, if no adverse effect is determined at block 2940 tohave occurred, then the current and/or a future second period can beshortened, i.e., the titration of the parameter may take place morerapidly than originally programmed if there are no significant adverseeffects.

Turning to FIG. 30, a simplified flowchart diagram for performing atitration process in accordance with some embodiments herein isillustrated. A dosage for providing a therapy may be determined, andbased upon the dosage, a titration regimen may be initiated (block3010). In some embodiments, the titration regimen is based upon thedosage and/or one or more specific characteristics of the patient, e.g.,patient tolerance level.

Upon performing one or more upward titration steps, one or more bodydata may be received and analyzed to determine whether there exists anadverse effect (block 3030). In other embodiments, an external sourcemay provide the medical device 2200 an indication of an adverse effect.For example, the patient may provide a manual input that is indicativeof an adverse effect. In other embodiment, the medical device 2200 mayreceive a signal from an external device, indicating an adverse effect.

Upon a determination that no adverse effect has been found (block 3030),the medical device may determine whether the final dosage has beenreached (block 3040). If the final dosage has been reached, the medicaldevice may stop the titration process and save the titration parameters(block 3050). Upon a determination that the final dosage has not beenreached (block 3040), the medical device may continue the titrationprocess (block 3020), e.g., by implementing a next titration step uponthe passage of a titration step interval. The process may continue aspreviously discussed (e.g., by returning to block 3030).

If the medical device 2200 determines that at least one adverse effecthas been found (block 3030), the medical device 2200 may implement amodification of the titration regimen (block 3060). This modificationmay be automatically performed based upon the type of adverse effectsdetected. Alternatively, or in addition, manual input from a person, orautomated input based upon body data, may also affect modification ofthe titration regimen.

Upon implementing the modified titration regimen, the medical device2200 may again determine whether an adverse effect has been found (block3070). If an adverse effect is found, the medical device 2200 may againimplement a modification of the titration regimen (as indicated by thepath from block 3070 to 3060). If an adverse effect is not found (block3070) and the final dosage has been reached (block 3080), the titrationprocess is terminated and the titration parameters are saved (block3050). If the final dosage has not been reached (block 3080), themedical device 2200 may continue the titration process, moving thetitration in the direction of the final dosage (see path from block 3080to 3020). In this manner, an automated and/or manual implementation of atitration regimen, moving upwardly towards the therapy dosage, isimplemented while reducing the risk of adverse effects.

Turning now to FIG. 31, a flowchart diagram for a method of implementinga titration interrupt and/or a multi-titration process, in accordancewith some embodiments is illustrated. Upon determining a dosage fortherapeutic treatment stimulation for a disease such as epilepsy, anon-event-specific state titration process may be initiated (block3110). The non-event-specific state titration process is performed toautomatically initiate a treatment regimen, to gradually reach a fulldosage regimen to treat a condition (e.g., epilepsy). Thenon-event-specific state titration is performed at pre-programmed timesand in pre-programmed steps independent of the occurrence of seizures,(e.g., open-loop process). That is, in some embodiments, thenon-event-specific state titration process may be not responsive to aparticular epileptic event. In one embodiment, the non-event-specificstate titration process may be implemented in the manner described inFIG. 30.

Continuing referring to FIG. 31, the medical device 2200 maycontinuously check to determine whether an epileptic event (e.g., aseizure, a fall associated with a seizure, an accident associated with aseizure, etc.) is detected (block 3120). If no epileptic events aredetected, the non-event-specific state titration process is continued(block 3130). If and when an epileptic seizure is detected, thenon-event-specific state titration process may be temporarilyinterrupted (block 3140). Upon interrupting the non-event-specific statetitration process, in one embodiment, the medical device 2200 mayimplement an event-specific therapy (block 3150) (e.g., closed-loop).The event-specific therapy may be a specific therapy regimen that isdirected to treat the specific type of event (e.g., seizure) that isdetected. For example a 1st therapy signal may be provided for aclinical seizure, while 2nd therapy may be provided for a sub-clinicalseizure. In other embodiment, a 1st therapy signal may be provided for ageneralized seizure, while a 2nd therapy signal may be provided for apartial seizure. In yet other embodiments, other distinctions forseizures (e.g., simple partial or complex partial or secondarilygeneralized seizure etc.) may be used to implement specific therapysignals tailored to address those distinctions. In some embodiment, alook-up function may be performed to select the various parameters(e.g., frequency, pulse-train parameters, pulse-width, inter-pulseinterval, amplitude, etc.) relating to the therapy signal. Theevent-specific therapy/titration process may be closed-loop process,specific to the treatment of the epileptic event, wherein this processterminates with the epileptic event.

In an alternative embodiment, upon interrupting the non-event-specificstate titration process (block 3140), an event-specific titrationprocess may be implemented (block 3160). The event-specific titrationprocess may provide for determining a dosage to treat the specificepileptic event that has been detected, and initiate a treatment regimenusing parameter settings that are increased to a full-dosage setting totreat the epileptic event. Upon implementing the event-specific (e.g.,closed-loop) titration process, the medical device 2200 may thenimplement an event-specific therapy based upon the event-specifictitration. In one embodiment, the time-periods relating to the step-wiseincreases in one or more parameters associated with the event-specifictitration process are equal to or larger than those relating to thenon-event-specific state titration process. The event-specifictherapy/titration process may be closed-loop process, specific to thetreatment of the detected epileptic event, wherein this processterminates with the epileptic event.

Upon performing either of the two processes of blocks 3140 and 3160(event-specific therapy or event-specific titration), the medical device2200 may determine whether the epileptic event had concluded orsufficiently subsided (block 3170). Upon a determination the epilepticevent has not sufficiently subsided, the event-specific therapy orevent-specific titration is continued (block 3180). Upon a determinationthe epileptic event has concluded or has sufficiently subsided, themedical device 100 may revert back to the non-event-specific statetitration process (block 3190).

In some embodiments, the present disclosure may relate to a method ofproviding a bringing an electrical stimulation regimen administered by amedical device to a target dosage, comprising programing a therapyregimen based upon at least one target electrical parameter; programmingone or more titration parameters for titrating to the target electricalparameter; initiating the electrical therapy at the programmed initialvalues; receiving a body signal after initiating the therapy at theprogrammed initial values; determining whether there is an adverseeffect associated with the therapy, based upon the body signal;adjusting one or more titration parameters to yield an adjustedtitration, in response to a determining that there is an adverse effectassociated with the therapy; implementing the adjusted titration, andtitrating the at least one target electrical parameter according to theadjusted titration.

Receiving the body signal may comprise receiving at least one ofautonomic data, neurological data, endocrine data, metabolic data,tissue stress marker data, responsiveness data, or physical fitnessdata.

Adjusting may comprise returning the electrical parameter value to aprior value. The adjusted therapy may be safe, efficacious, and/ortolerable.

This method may further comprise alerting a physician, in response to acardiac or respiratory adverse effect.

This method may further comprise determining an efficacy of the adjustedtherapy. This method may further comprise stopping the titration processand notifying a physician, in response to the adjusted therapy beingefficacious before the target parameter is reached.

In some embodiments, the target electrical parameter may be selectedfrom an amplitude, a pulse width, a pulse frequency, a signal on-time, awaveform, a level or degree of charge balance in a pulse, a polarity, asignal off-time, or two or more thereof. For example, adjusting thetherapy may comprise at least one of reducing an electrical currentamplitude of the electrical parameter, or determining a modifiedtitration function.

In some embodiments, increasing the electrical parameter value may beperformed during states in which taking said step is most comfortable orsafe. For a therapy such as vagus nerve stimulation that may causethroat discomfort or coughing, increasing the electrical parameter maybe performed while the patient is asleep when the discomfort or painthresholds are higher than during wakefulness. In some embodiments, thetitration may comprise detecting a patient state, where the patientstate is one or more of sleeping, awake, resting awake, sitting andawake, active and awake, and exercising. Detecting whether the patientis sleeping may further comprise detecting a sleep state of the patientselected from stage 1, stage 2, stage 3, stage 4, and REM sleep, lightsleep, and deep sleep. In some embodiments, where the electrical therapymay use bradycardia, increasing the electrical parameter value may takeplace only while the patient is awake to minimize the risk of notdetecting symptoms associated with the slowing down of the patient'sheart rate.

The electrical stimulation regimen of this method may be configured totreat epilepsy, depression, pain, congestive heart failure, traumaticbrain injury, or obesity.

In any of the automatic titration methods described herein, thetitration may be suspended at any step upon the detection of an acutemanifestation of the patient's illness, e.g., a seizure if the patientsuffers epilepsy, and an alternative, closed-loop therapy to treat theacute manifestation may be implemented. (The acute therapy may involve asecond titration process. Further, the second titration process may beimplemented by a function that uses as input(s) information regardingthe first titration process). Upon termination of the acutemanifestation, the titration may be resumed, typically at the step atwhich it was suspended. In some embodiments, however, the titration maybe resumed at a higher or lower step.

In some embodiments, a method is provided for performing an interruptionof a non-event specific titration process (e.g., open-loop) performed byan implanted medical device, comprising: a) programming the medicaldevice to provide an electrical therapy, wherein the programmedelectrical therapy comprises a first target value for a first electricaltherapy parameter defining the electrical therapy; b) programming atleast one titration parameter for automatically adjusting the firstelectrical therapy parameter from a first value to the first targetvalue over a titration time period of at least two days, wherein the atleast one titration parameter is selected from the titration timeperiod, a titration step interval, a titration step magnitude, and atitration step rate; initiating the electrical therapy, wherein thefirst electrical therapy parameter comprises said first value; c)automatically titrating the electrical therapy by making a plurality ofadjustments to the value of the first electrical therapy parameter,whereby the first electrical therapy parameter is changed from the firstvalue to a second target value according to a titration function; d)detecting an epileptic event; e) interrupting the open-loop titratingprocess in response to detecting an epileptic event; f) providing anevent-specific (e.g., closed-loop) therapy; and g) reverting back to thenon-event specific titration process in response to a determination thatthe epileptic event has concluded.

In other embodiments, a method is provided for performing aninterruption of a non-event specific titration process performed by animplanted medical device, comprising: a) performing a non-event specifictitration process; b) detecting an epileptic event; c) interrupting thenon-event specific titration process in response to detection theepileptic event; d) implementing an event-specific titration process fordelivering a therapy in response the detection of the epileptic event;and e) reverting back to the non-event specific titration process inresponse to a determination that the epileptic event has concluded.

In yet another embodiment, a method is provided for modifying atitration process for providing a therapy by a medical device (fullyimplanted, partially implanted or external to the patient) comprising:a) initiating a titration process to treat a chronic condition, whereinthe titration process includes programming at least one titrationparameter for automatically adjusting an electrical therapy parameterfrom a first value to the first target value over a titration timeperiod; b) determining whether an adverse effect resulting from thetitration has been found; c) modifying at least one parameter associatedwith the titration process; and d) implementing a modified titrationprocess. In some embodiments, the titration process and/or the modifiedtitration process is continued upon determining that a final dosage ofthe therapy had been reached.

The methods described above may be implemented by the medical device2200 and/or the medical device system 2251. The methods described abovemay be governed by instructions that are stored in a non-transitorycomputer readable storage medium and that are executed by, e.g., aprocessor 2217 of the medical device 2200.

The methods depicted in FIGS. 28-31 and/or described above may begoverned by instructions that are stored in a non-transitory computerreadable storage medium and that are executed by, e.g., a processor 2217of the medical device 2200. Each of the operations shown in FIGS. 28-31and/or described above may correspond to instructions stored in anon-transitory computer memory or computer readable storage medium. Invarious embodiments, the non-transitory computer readable storage mediumincludes a magnetic or optical disk storage device, solid state storagedevices such as flash memory, or other non-volatile memory device ordevices. The computer readable instructions stored on the non-transitorycomputer readable storage medium may be in source code, assemblylanguage code, object code, or other instruction format that isinterpreted and/or executable by one or more processors.

In one embodiment, a method of treating a medical condition in a patientusing an implantable medical device, the implantable medical deviceincluding a first electrode coupled to a first cranial nerve structureand a second electrode coupled to a second cranial nerve structure,where the first cranial nerve structure is a left portion of a cranialnerve and the second cranial nerve structure is a right portion of thecranial nerve, the method may include: providing a first electricalsignal to the first cranial nerve structure of the patient using a firstpolarity configuration in which the first electrode functions as acathode and the second electrode functions as an anode, the firstelectrical signal is configured to induce action potentials in the firstcranial nerve structure, wherein a charge accumulates at the anode andthe cathode as a result of the first electrical signal, the firstelectrical signal utilizing a titrating procedure to reach a targetvalue; switching from the first polarity configuration to a secondpolarity configuration upon termination of the first electrical signalwhere the first electrode functions as the anode and the secondelectrode functions as the cathode in the second polarity configuration;and/or providing a second electrical signal to the second cranial nervestructure in the second polarity configuration, the second electricalsignal is configured to induce action potentials in the second cranialnerve structure where at least a portion of the second electrical signalcomprises the accumulated charge from the first electrical signal.

In addition, the method may include initiating a second titration periodfor a second therapy with a second treatment period; initiating a thirdtherapy based on an acute event detection; and/or initiating a secondtherapy based on an acute event detection. Further, one or more changesin one or more values associated with one or more parameters during afirst titration period do not cause an adverse effect. In addition, themethod may receive an input from the patient where the input obtainedfrom the patient occurs via a magnetic sensor input. Further, one ormore processors of the implantable medical device may modify at leastone of a first titration period and a modification procedure of one ormore values associated with one or more parameters based on at least oneof a patient's age, a patient's level of consciousness, a patient'slevel of attention, a patient's health status, a patient's gender, aseverity of a disorder being treated, a patient's tolerance to one ormore adverse events, and/or a patient's tolerance to pain. In addition,the method may include: initiating via one or more processors of theimplantable medical device a second titration period for a secondtherapy with a second treatment period, the second therapy including asecond electrical stimulation with a second set of parameters;initiating a second modification procedure based on the second set ofparameters with a second set of target values; and/or initiating thesecond therapy for the second treatment period based on at least oneparameter of the second set of parameters being tolerated by the patientor reaching at least one of the second set of target values. Further,the one or more processors of the implantable medical device may modifyat least one of a first titration period and a modification procedure ofone or more values associated with the one or more parameters based onat least one of an emergence of one or more side effects, a level ofefficacy, and an event detection. In addition, the event detection maybe an acute event detection. The method may include acquiring data forat least one of a status report, a historical report, and an alert andtransmitting the acquired data or the alert to an external device.Further, the one or more processors may modify at least one of thetitration period and a modification procedure of one or more valuesassociated with one or more parameters based on the patient beingasleep.

In another embodiment, a method of treating a medical condition in apatient using an implantable medical device, the implantable medicaldevice including a first electrode coupled to a first cranial nervestructure and a second electrode coupled to a second cranial nervestructure, where the first cranial nerve structure is a left portion ofa cranial nerve and the second cranial nerve structure is a rightportion of the cranial nerve, the method may include: providing a firstelectrical signal to the first cranial nerve structure of the patientusing a first polarity configuration in which the first electrodefunctions as a cathode and the second electrode functions as an anode,the first electrical signal is configured to induce action potentials inthe first cranial nerve structure, wherein a charge accumulates at theanode and the cathode as a result of the first electrical signal, thefirst electrical signal utilizing a titrating procedure to reach atarget value; switching from the first polarity configuration to asecond polarity configuration upon termination of the first electricalsignal where the first electrode functions as the anode and the secondelectrode functions as the cathode in the second polarity configuration;and/or providing a second electrical signal to the second cranial nervestructure in the second polarity configuration, the second electricalsignal is configured to induce action potentials in the second cranialnerve structure where at least a portion of the second electrical signalcomprises the accumulated charge from the first electrical signal wherea titration time interval is a time associated with the adverse effectnot recurring in response to an electrical stimulation using anelectrical stimulation value, where the electrical stimulation value hadpreviously elicited an adverse effect.

In addition, a time of a resumption of a titration process for the firstelectrical signal is based on at least one of: a patient's age, apatient's health status, a severity of the adverse effects, and/or aseverity of seizures. Further, an upward titration to a seizure valuemay be implemented in a transient period in response to a seizuredetection where the seizure value utilized for the upward titration is avalue which was intolerable during a non-seizure period. In addition,the method may include accelerating a titration process based onachieving a first target value without adverse effects. Further, atitration function may be non-uniform. Further, a titration parameter, atitration function and a titration period may utilize different valuesduring a wakefulness period and a sleep period. In addition, the atleast one body signal is an evoked response. Further, the method mayinclude determining a seizure severity and/or selecting at least one of:a titration function and a titration period based on the seizureseverity determination.

What is claimed:
 1. A method of treating a medical condition in apatient using an implantable medical device, the implantable medicaldevice including a first electrode coupled to a first cranial nervestructure and a second electrode coupled to a second cranial nervestructure, where the first cranial nerve structure is a left portion ofa cranial nerve and the second cranial nerve structure is a rightportion of the cranial nerve, the method comprising: providing a firstelectrical signal to the first cranial nerve structure of the patientusing a first polarity configuration in which the first electrodefunctions as a cathode and the second electrode functions as an anode,the first electrical signal is configured to induce action potentials inthe first cranial nerve structure, wherein a charge accumulates at theanode and the cathode as a result of the first electrical signal, thefirst electrical signal utilizing a titrating procedure to reach atarget value; switching from the first polarity configuration to asecond polarity configuration upon termination of the first electricalsignal where the first electrode functions as the anode and the secondelectrode functions as the cathode in the second polarity configuration;and providing a second electrical signal to the second cranial nervestructure in the second polarity configuration, the second electricalsignal is configured to induce action potentials in the second cranialnerve structure where at least a portion of the second electrical signalcomprises the accumulated charge from the first electrical signal. 2.The method of claim 2, further comprising initiating a second titrationperiod for a second therapy with a second treatment period.
 3. Themethod of claim 2, further comprising initiating a third therapy basedon an acute event detection.
 4. The method of claim 1, furthercomprising initiating a second therapy based on an acute eventdetection.
 5. The method of claim 1, wherein one or more changes in oneor more values associated with one or more parameters during a firsttitration period do not cause an adverse effect.
 6. The method of claim1, further comprising receiving an input from the patient where theinput obtained from the patient occurs via a magnetic sensor input. 7.The method of claim 1, wherein the one or more processors of theimplantable medical device modifies at least one of a first titrationperiod and a modification procedure of one or more values associatedwith one or more parameters based on at least one of a patient's age, apatient's level of consciousness, a patient's level of attention, apatient's health status, a patient's gender, a severity of a disorderbeing treated, a patient's tolerance to one or more adverse events, anda patient's tolerance to pain.
 8. The method of claim 1, furthercomprising: initiating via one or more processors of the implantablemedical device a second titration period for a second therapy with asecond treatment period, the second therapy including a secondelectrical stimulation with a second set of parameters; initiating asecond modification procedure based on the second set of parameters witha second set of target values; and initiating the second therapy for thesecond treatment period based on at least one parameter of the secondset of parameters being tolerated by the patient or reaching at leastone of the second set of target values.
 9. The method of claim 1,wherein the one or more processors of the implantable medical devicemodifies at least one of a first titration period and a modificationprocedure of one or more values associated with the one or moreparameters based on at least one of an emergence of one or more sideeffects, a level of efficacy, and an event detection.
 10. The method ofclaim 9, wherein the event detection is an acute event detection. 11.The method of claim 1, further comprising acquiring data for at leastone of a status report, a historical report, and an alert andtransmitting the acquired data or the alert to an external device. 12.The method of claim 1, wherein the one or more processors modifies atleast one of the titration period and a modification procedure of one ormore values associated with one or more parameters based on the patientbeing asleep.
 13. A method of treating a medical condition in a patientusing an implantable medical device, the implantable medical deviceincluding a first electrode coupled to a first cranial nerve structureand a second electrode coupled to a second cranial nerve structure,where the first cranial nerve structure is a left portion of a cranialnerve and the second cranial nerve structure is a right portion of thecranial nerve, the method comprising: providing a first electricalsignal to the first cranial nerve structure of the patient using a firstpolarity configuration in which the first electrode functions as acathode and the second electrode functions as an anode, the firstelectrical signal is configured to induce action potentials in the firstcranial nerve structure, wherein a charge accumulates at the anode andthe cathode as a result of the first electrical signal, the firstelectrical signal utilizing a titrating procedure to reach a targetvalue; switching from the first polarity configuration to a secondpolarity configuration upon termination of the first electrical signalwhere the first electrode functions as the anode and the secondelectrode functions as the cathode in the second polarity configuration;and providing a second electrical signal to the second cranial nervestructure in the second polarity configuration, the second electricalsignal is configured to induce action potentials in the second cranialnerve structure where at least a portion of the second electrical signalcomprises the accumulated charge from the first electrical signal;wherein a titration time interval is a time associated with the adverseeffect not recurring in response to an electrical stimulation using anelectrical stimulation value, where the electrical stimulation value hadpreviously elicited an adverse effect.
 14. The method of claim 13,wherein a time of a resumption of a titration process for the firstelectrical signal is based on at least one of: a patient's age, apatient's health status, a severity of the adverse effects, and aseverity of seizures.
 15. The method of claim 13, wherein an upwardtitration to a seizure value is implemented in a transient period inresponse to a seizure detection where the seizure value utilized for theupward titration is a value which was intolerable during a non-seizureperiod.
 16. The method of claim 13, further comprising accelerating atitration process based on achieving a first target value withoutadverse effects.
 17. The method of claim 13, wherein a titrationfunction is non-uniform.
 18. The method of claim 13, wherein a titrationparameter, a titration function and a titration period utilize differentvalues during a wakefulness period and a sleep period.
 19. The method ofclaim 13, wherein the at least one body signal is an evoked response.20. The method of claim 13, further comprising determining a seizureseverity and selecting at least one of: a titration function and atitration period based on the seizure severity determination.